Phytochemicals as Radioprotective and Radiosensitizing Agents in Cancer Radiotherapy: Advances, Challenges, and Future Perspectives

Abstract

Radiation therapy (RT) remains a fundament of cancer treatment, yet its effectiveness is often hindered by normal tissue toxicity and radiation-induced fibrosis. Recent research has highlighted the promise of bioactive-phytochemicals in enhancing the therapeutic index of RT-sensitizing tumor cells to radiation while safeguarding healthy tissues. This reflects a growing interest in integrating natural compounds with conventional cancer therapies to achieve synergistic effects. To summarize recent advances, identify the research gaps, and evaluate future directions, a comprehensive review was conducted using data from the NCBI and PubChem databases, focusing on preclinical and clinical studies exploring the role of phytochemicals in cancer radiotherapy. The findings stated that the phytochemicals such as curcumin, resveratrol, quercetin, genistein, and EGCG have been shown to sensitize cancer cells to radiation by amplifying DNA damage, promoting apoptosis, and inhibiting key signaling pathways including PI3K/Akt, ATM, and NF-κB. Simultaneously, these compounds exhibit protective effects on normal tissues by activating antioxidant responses (e.g., Nrf2/ARE), reducing oxidative stress, and alleviating radiation-induced fibrosis through modulation of CTGF and TGF-β pathways. Emerging agents like astilbin, puerarin, and isorhamnetin have also demonstrated notable radiosensitizing and antifibrotic potential. However, challenges such as poor bioavailability, dose inconsistencies, and patient-specific variability remain significant barriers to clinical translation. In conclusion, the dual context-dependent actions of phytochemicals emphasize the need for personalized therapeutic strategies, optimized dosing, and advanced delivery systems. Furthermore, integrating nanotechnology may hold particular promise for enhancing the precision and effectiveness of phytochemical-based interventions in radiation oncology.

Keywords

phytochemicals - radioprotector - radiosensitizer - personalized medicine - cancers

Abbreviations

AMPK: AMP-Activated Protein Kinase

ATM: Ataxia Telangiectasia Mutated

Bcl-2: B-cell Lymphoma 2

BRCA1: Breast Cancer Type 1 Susceptibility Protein

CDKs: Cyclin-Dependent Kinases

CTGF: Connective Tissue Growth Factor

DNA-PK: DNA-Dependent Protein Kinase

ECM: Extracellular Matrix

EGCG: Epigallocatechin-3-Gallate

ERK: Extracellular Signal-Regulated Kinase

FOXO: Forkhead Box O

IL: Interleukin

IMRT: Intensity-Modulated Radiation Therapy

JNK: c-Jun N-terminal Kinase

MAPK: Mitogen-Activated Protein Kinase

MMP: Matrix Metalloproteinases

mTOR: Mechanistic Target of Rapamycin

NF-κB: Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells

Nrf2: Nuclear Factor Erythroid 2–Related Factor 2

PARP: Poly (ADP-Ribose) Polymerase

PDGF: Platelet-Derived Growth Factor

PI3K: Phosphoinositide 3-Kinase

ROS: Reactive Oxygen Species

SMA: Smooth Muscle Actin

STAT3: Signal Transducer and Activator of Transcription 3

TBI: Total Body Irradiation

TGF-β : Transforming Growth Factor Beta

TIMPs: Tissue Inhibitors of Metalloproteinases

TNF-α : Tumor Necrosis Factor Alpha

YAP/TAZ: Yes-Associated Protein/Transcriptional Co-Activator with PDZ-Binding Motif
 

Introduction

Radiation therapy (RT) is a clinical modality utilizing ionizing radiation to kill growing and dividing tumor cells [1]. RT originated in Wilhelm Roentgenʼs discovery of X-rays in 1895, causes DNA damage by breaking molecules and inducing clastogenic lesions that inhibit cancer cell division and growth, and results in tumor destruction. RT efficacy is based on administered dose and the amount of radiation interaction with cellular structures. RT is delivered in several forms, such as X-rays and gamma rays [2], and is frequently combined with other therapies for cancer to reduce tumors before surgery and treat advanced disease symptoms [3]. Although mainly affecting tumor cells, RT also hits adjacent healthy tissue, causing collateral damage because of its local and systemic effects. As opposed to chemotherapy, RT has a localized treatment method; however, normal tissue toxicity is still a serious issue.

Cancer is one of the global leading causes of morbidity and mortality, estimated to have recorded 20 million new cases and 9.7 million deaths in 2022. Over 50% of cancer patients need RT incorporated into their therapeutic regimen (NCI cancer stats, 2024), illustrating the imperative need for effective interventions that increase efficiency with fewer adverse effects. One of the main disadvantages of RT is the risk for the development of fibrosis, a late effect that occurs due to radiation-induced injury in adjacent healthy tissues [4]. This can lead to the buildup of excessive fibrous connective tissue, potentially compromising organ function and causing persistent symptoms that significantly affect a patientʼs quality of life [5]. RT also carries risks of secondary malignancies through radiation-induced genetic mutations. Differences in how patients respond to treatment make it harder to predict outcomes, highlighting the need for personalized treatment planning [6].

Bioactive phytochemicals, once primarily known for their role in protecting plants against pathogens, are now being actively studied for their medicinal potential, particularly their anti-cancer properties. These include the inhibition of carcinogen activation, prevention of oxidative damage, modulation of critical signaling pathways, and regulation of oncogenic gene expression [7]. Notably, their low toxicity profile makes them attractive candidates for inclusion in combination cancer therapies. The addition of phytochemicals to RT has shown synergistic effects with promising results, increasing cancer cell radiosensitivity to radiation-induced damage. For example, Genistein has been reported to augment radiation effects by blocking DNA repair mechanisms, enhancing tumor radiosensitivity while providing radioprotection to normal tissues [8]. Quercetin also modulates PI3K/Akt signaling, sensitizing the tumor cells while showing protective effects in non-cancerous tissues. In addition, curcumin, although highly anti-cancer in nature, has bioavailability issues, which have led to investigations into nanoparticle-based drug delivery systems to enhance its therapeutic utility [9].

The dual functionality of phytochemicals in radiotherapy–sensitizing cancer cells while protecting normal tissues–is underpinned by distinct but overlapping molecular mechanisms. As radiosensitizers, certain phytochemicals interfere with tumor cell repair pathways, for instance, compounds like genistein inhibit DNA repair mechanisms by suppressing the activity of key kinases such as DNA-PKcs and ATM, leading to persistence of DNA double-strand breaks after radiation exposure [10]. It has been shown to also downregulate RAD51, impairing homologous recombination repair and tipping the balance toward apoptosis. Quercetin, by targeting the PI3K/Akt axis, prevents phosphorylation of Akt at Ser473, thereby inactivating downstream anti-apoptotic proteins like Bcl-2 and mTOR and enabling activation of pro-apoptotic mediators such as Bax and caspase-3 to enhance mitochondrial outer membrane permeabilization and initiate intrinsic apoptosis in cancer cells. As radioprotectors, phytochemicals activate Nrf2 (nuclear factor erythroid 2–related factor 2) by disrupting its repressor, Keap1, through oxidative or electrophilic modification of its cysteine residues [11]. Once freed, Nrf2 translocates into the nucleus, where it binds to antioxidant response elements (AREs) and upregulates genes such as SOD1, HO-1, and GPx, reinforcing antioxidant defenses in healthy cells. Curcumin, for instance, boosts the Nrf2-ARE axis while simultaneously inhibiting NF-κB nuclear translocation by blocking phosphorylation of its inhibitor IκBα, reducing radiation-induced inflammation [12], [13].

Phytochemicals offer additional benefits by targeting multiple cancer progression pathways, counteracting resistance mechanisms that often develop in single-target therapies ([Table 1] and [2]). Their availability through dietary intake or as herbal supplements makes them appealing to patients seeking complementary and integrative treatments. Moreover, the variability in phytochemical responses based on genetic and molecular factors presents a compelling case for personalized medicine approaches in cancer treatment [14]. This review provides new insights into the role of phytochemicals in enhancing radiation therapy efficacy, focusing on context-dependent mechanisms, mitigation of radiation-induced fibrosis, and innovative clinical applications. It explores how phytochemicals function as both radiosensitizers and radioprotectors, depending on factors such as tumor type and molecular pathways, as well as integrative insights from clinical trials, preclinical studies, and mechanistic analyses.

Table 1 Current Status of Phytochemical-Based Clinical Trials in Cancer:

Name of the Extract/Phytochemical & (Study NCT Number)	Cancer Type(s)	Study Status	Clinical Phase	Start Date (MM-YYYY)	End Date (MM-YYYY)	Results	Novel Insights	Potential Clinical Translation
Grape Seed Extract (NCT01820299)	Solid Cancers	completed	Phase I	03 – 2013	05 – 2016	Established maximally tolerated dose (MTD) and safety profile of GSE in advanced solid tumors; no efficacy outcomes reported.	Uses proanthocyanidin-rich extract to modulate systemic inflammation in advanced cancers.	May serve as an adjuvant to reduce RT-induced inflammation and improve patient tolerance.
Genistein + Omega-3 PUFA (NCT00433797)	Prostate Cancer	completed	Phase I/II	06 – 2007	12 – 2013	Dietary intervention using tomato and multi-diet phytochemical/PUFA regimens for 3 weeks modestly reduced PSA levels and improved antioxidant and anti-inflammatory biomarkers in localized prostate-cancer patients compared with controls.	Combines tyrosine kinase inhibition with lipid-mediated eicosanoid modulation.	Could offer dual anti-inflammatory and anti-proliferative effects in prostate RT protocols.
Ferulic Acid, Caffeic Acid (Wheat-Bran-derived) (NCT02177279)	N/A (Bioavailability study)	completed	N/A	12 – 2011	02 – 2013	Wheat bran phytochemicals were rapidly absorbed and metabolized within 24 hours, showing good bioavailability and potential anti-inflammatory and antioxidant effects.	Tracks systemic absorption and metabolism of potent dietary antioxidants.	Enables formulation optimization for higher delivery during RT.
Curcumin + Ursolic Acid (NCT04403568)	Prostate Cancer	withdrawn	Early Phase I	10 – 2021	12 – 2023	The combination of curcumin and ursolic acid was well tolerated, with measurable serum and prostate tissue levels, confirming safety and bioavailability for further clinical evaluation.	Targets NF-κB and STAT3 simultaneously for enhanced anti-tumor activity.	Potential for RT synergy in hormone-refractory prostate cancer if formulation challenges are resolved.
Resveratrol + Docetaxel (NCT01012141)	Metastatic Prostate Cancer	completed	Phase II	09 – 2009	04 – 2011	Combination of docetaxel with a dietary phytochemical showed manageable safety and clinical activity in metastatic hormone-independent prostate cancer, with acceptable toxicity and evidence of treatment response.	Explores microtubule disruption plus PI3K/Akt inhibition.	May help reverse RT resistance in metastatic prostate tumors.
Anthocyanins, Ellagic Acid (Black Raspberry) (NCT02439255)	N/A (Oral Microbiome in Smokers)	completed	N/A	12 – 2015	04 – 2022	Black raspberry phytochemicals favorably modulated the oral microbiome in smokers, reducing microbial imbalance and restoring beneficial community profiles, suggesting protective effects against smoking-induced dysbiosis and oral cancer risk.	Links dietary polyphenols to oral microbiome shifts.	Could be incorporated into post-RT care to restore healthy oral ecology.
(Cyanidin-3-O-rutinoside, cyanidin-3-O-glucoside Lyophilized Black Raspberry (NCT01823562)	Stage I – III Prostate Cancer	active, not recruiting	Phase I	10 – 2012	06 – 2025 (estimated)	No results posted as of March 2025; trial focuses on safety/compliance and BRB metabolite absorption (urine/prostate tissue.	Measures bioavailability during surgical windows.	Sets pharmacokinetic groundwork for adjuvant RT dosing.
Curcumin + Docetaxel (NCT00852332)	Breast Cancer	terminated	Phase II	08 – 2009	11 – 2011	Trial terminated for futility–interim analysis showed no efficacy advantage for adding the phytochemical to docetaxel; no results posted.	Investigates curcuminʼs sensitizing effect on taxane chemotherapy.	Mechanistic overlap with RT makes it a candidate for concurrent regimens.
Black Raspberry Confection (Anthocyanins) (NCT01961869)	N/A (Oral Cancer Prevention)	active, not recruiting	Phase I	07 – 2013	07 – 2025 (estimated)	All black raspberry confection formulations were well tolerated; optimal bioavailability and gene expression modulation were observed with intermediate-release formulations.	Delivers polyphenols in palatable form for long-term prevention.	May improve adherence in head-and-neck RT survivors.
Sulforaphane (NCT03232138)	Lung Cancer	completed	Phase II	01 – 2018	02 – 2023	12-month oral sulforaphane significantly reduced bronchial Ki-67 versus placebo; no significant change in bronchial dysplasia; safety acceptable.	Uses Nrf2 activation for secondary cancer prevention.	Could be applied to protect lung tissue during thoracic RT.
Black Raspberry Nectar (NCT04267874)	Lung Carcinoma	completed	Early Phase I	10 – 2019	06 – 2021	No results posted; feasibility of BRB nectar intervention assessed with microbiome and inflammatory biomarker endpoints (completed 2021).	Targets oxidative stress in lung tissue via dietary delivery.	RT-protective strategy for lung parenchyma.
Berry Powder (NCT00681512)	Non-Small Cell Lung Cancer	terminated	N/A	04 – 2008	12 – 2013	Study terminated early due to low participant enrollment; no efficacy data reported on berry powder effects in NSCLC patients.	High-anthocyanin intervention in lung cancer.	Potential adjuvant for lung RT pending formulation optimization.
Tomato-Soy Juice (NCT01009736)	Prostate Cancer	completed	Phase I/II	01 – 2008	07 – 2009	Tomato-soy juice was well tolerated and significantly increased plasma and urinary levels of lycopene, β-carotene, and soy isoflavones. The intervention showed favorable modulation of oxidative stress and hormone-related biomarkers, suggesting potenzial prostate cancer preventive effects.	Combines lycopene (DNA protection) with isoflavones (hormonal modulation).	Could reduce oxidative DNA damage during pelvic RT.
Quercetin + Genistein (NCT01538316)	Prostate Cancer Prevention	unknown	N/A	03 – 2012	04 – 2014	No results posted; study status last verified in 2012 (unknown current status). Effect of quercetin/genistein on PSA slope undetermined.	Was proposed for flavonoid combination targeting PI3K and tyrosine kinase pathways.	May lower tumor initiation risk in high-risk RT candidates.
Sulforaphane (NCT03934905)	Breast Cancer (Cardiotoxicity Prevention)	recruiting	Phase I/II	06 – 2022	06 – 2026 (estimated)	Ongoing; no results posted yet. Efficacy and cardioprotection of sulforaphane during doxorubicin therapy not yet determined.	Aimed at protecting cardiac tissue via Nrf2 pathway.	Directly relevant to cardioprotection during left-sided breast RT.

Table 2 Expanded Clinical Trials of Phytochemicals in Cancer Therapy, Contextual Implications for Radiotherapy, and Analysis of Key Limitations:

NCT No. & Phytochemical Name	Clinical Phase	Cancer Type	No. of Enrollment	Dose(s)	Study Outcome	Implications	Limitations	Strategies Against Limitations
NCT03980509 Curcumin	Completed	Breast Cancer	22	2 grams of oral curcumin daily for 14 days	Curcumin was safe and activated immunity in breast cancer patients in their blood samples.	Poised to inhibit IKK (IκB kinase) to boost NF-κB; variable exposure (5 – 56 days) to curcumin 500 mg BID; assesses only pre/post-tumor biomarkers (Ki-67, apoptosis) without a control or clinical outcomes–high risk of bias (sampling variability, regression to the mean) and limited generalizability.	Small sample size; short exposure period; no clinical endpoints like tumor response; limited to immunological biomarkers.	Expand to multi-center RCTs with RT arm; integrate immune activation markers and tumor regression outcomes.
NCT01042938 Curcumin	Completed	Breast Cancer	35	6.0 g/day oral curcumin	Curcumin reduced radiation dermatitis severity in patients with noninflammatory breast cancer or ductal carcinoma in situ.	Mitigates radiation-induced skin toxicity. Randomized, double-blind, placebo-controlled pilot (n = 35, single-center) during adjuvant breast RT–strong internal validity (quadruple blinding; objective colorimetry) but underpowered with short follow-up focused on acute dermatitis (RDS, redness, pain) only; strict exclusions and a high oral curcumin dose with low bioavailability limit generalizability and clinical interpretability.	No long-term follow-up; high oral dose may affect compliance; lacks mechanistic biomarker validation.	Test-optimized dosing schedules; incorporate long-term skin quality scoring and inflammatory biomarker tracking.
NCT00256334 Resveratrol	Completed	Colon Cancer	11	450 – 3600 mg/day orally up to 4 months	Curcumin was well-tolerated with modulation of inflammatory biomarkers in 15 patients with advanced colorectal cancer.	Suggests anti-inflammatory effects via eicosanoid pathway modulation.	Very small cohort; no tumor outcome measures; heterogeneous dosing; unclear optimal therapeutic window.	Conduct larger prevention trials; measure both systemic and tissue-level anti-inflammatory effects during RT.
NCT00433576 Resveratrol	Completed	Colon/Rectal Cancer	20	2 g/day and 4 g/day orally	Curcumin reduced ACF number by 40%; no change in PGE2, 5-HETE, or Ki-67 in smokers with early sign of precancerous lesions (ACF) in the colon.	Suggests potential chemo-preventive effect via anti-inflammatory pathways. Open-label, single-arm perioperative phase I (n = 20). Probing short-course oral resveratrol PK/PD with paired pre/post tissue biopsies–strong mechanistic design but no comparator, tiny sample, 8-day exposure, and biomarker-only endpoints; strict exclusions further limit generalizability, so efficacy cannot be inferred.	Surrogate endpoint may not predict cancer incidence; lack of long-term cancer outcomes; smoker-specific findings limit generalizability.	Link ACF reduction to long-term incidence; explore combination with dietary modulation for additive effect.
NCT00920556 Resveratrol	Terminated	Multiple Myeloma	24	450 – 3600 mg/day orally	Curcumin was well-tolerated with modulation of inflammatory biomarkers.	Suggests anti-inflammatory effects via eicosanoid pathway modulation. Open-label, single-arm phase II (n = 24; terminated early) of high-dose oral SRT501 with protocol-triggered bortezomib–appropriate for safety-signal-finding but no control and mid-course treatment changes confound efficacy; planned PK was largely unrealized; small, heterogeneous cohort limits precision and generalizability.	Terminated before completion; no efficacy data; possible recruitment/feasibility issues.	Address feasibility via flexible recruitment criteria; consider surrogate biomarkers for early efficacy signals.
NCT01985763 Genistein	Completed	Colorectal Cancer	13	300 mg orally once daily	Genistein was well-tolerated in patients with metastatic colorectal cancer.	Single-center, open-label phase I/II (n = 13) adding intermittent low-dose genistein to FOLFOX±bevacizumab–powered for tolerability, not efficacy; no control arm and very small sample preclude causal inference on RECIST/PFS; heterogeneous backbone therapy and short exposure limit generalizability; biologic rationale: genistein may inhibit Wnt signaling, frequently activated in colorectal cancer.	Small, non-randomized study; no control arm; absence of progression-free or overall survival data.	Combine with RT in Wnt-activated tumors; explore synergy with DNA damage modulators.
NCT00844792 Lycopene	Completed	Prostate Cancer	48	Vitamin E (400 IU), Selenium (200 mcg), Lycopene (15 mg) daily for 8 weeks	Result not posted; the study aims to assess if antioxidants (Vitamin E, Selenium, Lycopene) reduce prostate tumor size and alter growth/aggressiveness markers.	Randomized, double-blind, single-center phase 2 “window” trial (n = 48) giving a 5-component antioxidant cocktail (lycopene, vitamin E, selenium, vitamin D3, green tea) for 6 – 8 weeks pre-prostatectomy; powered for tumor size/biomarker shifts, not clinical outcomes. Very small sample, short exposure, and multi-ingredient formulation limit power, mechanistic attribution, and external validity; no posted results. Potential antioxidant-mediated modulation of oxidative stress and androgen-related pathways in prostate cancer progression.	Lack of posted outcomes; possible non-publication bias; no RT-specific endpoints; unclear compliance monitoring.	Repeat with strict adherence monitoring; test sequential antioxidant timing to avoid tumor protection during RT.
NCT03232138 Sulforaphane	Completed	Lung Cancer	43	120 µmol SF daily for 12 months	Modulated bronchial dysplasia, decreased Ki-67, increased apoptosis, downregulated oncogenes in former smokers who are at high risk for lung cancer.	Randomized, quadruple-blind, single-center phase 2 chemoprevention trial in former smokers (n = 43) giving high-dose sulforaphane for 12 months (≈ 240 µmol/day) with rigorous surrogate endpoints (bronchial dysplasia index; Ki-67/TUNEL/caspase-3; airway/nasal gene-expression signatures). Strengths: parallel design, protocolized paired bronchoscopies, and results posted. Mechanistically, epigenetic modulation, inhibition of cell proliferation, induction of apoptosis, suppression of lung cancer-related genes.	Biomarker-only endpoints; no survival or progression data; bioavailability variability not controlled.	Add survival endpoints; stratify by smoking history and integrate pulmonary RT cohorts.
NCT01228084 Sulforaphane	Completed	Prostate Cancer	60	Sulforaphane (SF) for up to 20 weeks	Proportion of patients achieving 50% PSA decline, decrease in PSA levels, and no PSA doubling.	Single-arm, open-label pilot (n = 20) using short-term PSA decline as a surrogate–no control, small sample, and 20-week follow-up make efficacy inference weak; strengths are prospective PK/PD and safety readouts, but no clinical endpoints (MFS/OS). Potential anti-tumor activity through PSA reduction, targeting prostate cancer progression by inhibiting tumor growth or recurrence pathways.	PSA decline not directly correlated with long-term clinical outcomes; no imaging or survival metrics.	Include MRI/PSMA PET; long-term biochemical recurrence tracking.
NCT00843167 Sulforaphane	Completed	Breast Cancer	54	Broccoli sprout extract for up to 8 weeks	Measurement of isothiocyanates, Ki-67, and HDAC activity changes in blood cells in women with breast cancer, ductal carcinoma in situ (DCIS).	Testing broccoli-sprout-derived sulforaphane for 2 – 8 weeks with mechanistic endpoints (urinary isothiocyanates, PBMC HDAC activity, Ki-67). Strengths: rigorous blinding, tissue/blood biomarker readouts, adherence tracking. Potential anti-cancer activity through modulation of tumor markers (Ki-67) and epigenetic regulation (HDAC activity) in breast cancer and precancerous conditions.	Short duration; no tumor shrinkage or survival outcomes; dietary variability may confound results.	Extend duration; pair with neoadjuvant RT to measure impact on tumor size and histology.
NCT01070355 Omega-3 Fatty Acids	Completed	Colorectal Cancer	88	Dose not specified. Treatment for 4 weeks before surgery	Histological evaluation of Ki67 proliferation, neo-CK18 apoptosis, CD31 micro vessel density, and various plasma markers for prostaglandin metabolism.	EPA rapidly incorporated into tumor tissue and lowered intratumoral PGE₂; coupled with preclinical COX-2/PGE₂ biology linking PGE₂ suppression to reduced proliferation and increased apoptosis; this supports the proposed mechanism. Eicosatetraenoic acid (EPA) may reduce tumor growth in colorectal cancer liver metastases through inhibition of cancer cell proliferation, induction of apoptosis, and modulation of prostaglandin metabolism.	Short-term preoperative study; unclear dose; no post-surgical recurrence or survival data.	Extend supplementation through RT; correlate dose with prostaglandin pathway suppression.
NCT00773955 R-(−)-Gossypol acetic acid	Phase I/II	Multiple Solid Tumors	50	Variable oral dosing	Bcl-2 inhibition-related apoptosis in advanced solid tumors.	The trial evaluated a BH3-mimetic BCL-2–family inhibitor; by antagonizing anti-apoptotic proteins (BCL-2/BCL-XL/MCL-1); it lowers the apoptotic threshold in tumor cells. It could radiosensitize tumors by lowering anti-apoptotic threshold.	Single arm, heavily pretreated patients; no RT added; toxicity and PK poorly characterized.	Optimize PK with nanoformulations; evaluate in RT-resistant tumors.
NCT00524524 β-Lapachone	Phase I	NQO1-Overexpressing Tumors	40	Intermittent IV dosing	ROS-mediated apoptosis in NQO1+ patients.	Tested β-lapachone (ARQ-501), an NQO1-activated drug that generates high ROS and extensive DNA damage (via PARP hyperactivation) in NQO1-high tumors insightful for use in tumors with oxidative stress to enhance RT-induced DNA damage.	Limited cohort, NQO1 stratification not standardized; no radiation combination arm.	Test in RT+oxidative stress protocols; NQO1 screening standardization.
NCT00701987 Betulinic acid ointment	Phase I	Cutaneous Metastatic Melanoma	30	Topical application	Local tumor necrosis in melanoma lesions.	A phase I trial of the topical melanoma agent ALS-357 showed feasible dermal delivery with acceptable local tolerability and skin-level pharmacodynamic activity in cutaneous lesions. It could be adapted for skin toxicity prevention during external beam RT.	Topical route limits systemic bioavailability; not tested with irradiation context.	Develop injectable forms for systemic radiosensitization.
NCT03569345 Ingenol mebutate	Phase I/II	Basal Cell Carcinoma	25	Topical PEP-005	Local lesion regression; apoptosis via PKC activation.	Trial evaluated ablative fractional laser–assisted delivery of topical ingenol mebutate for superficial basal cell carcinomas, showing feasible, high local cutaneous uptake. This can be a practical model for topical normal-tissue modifier during superficial RT.	FDA-approved for actinic keratosis, not cancer RT; systemic effects unknown; no RT data.	Formulate systemic analogs; test for mucosal RT protection.
NCT02891538 Epigallocatechin-3-gallate (EGCG)	Phase I	Colorectal Cancer Surgery	30	Oral EGCG pre-surgery	Decreased Ki-67 in tissue; antioxidant biomarker modulation.	EGCG was tested in CRC patients to modulate colonic mucosal inflammation/oxidative-stress biomarkers; this mechanism (anti-inflammatory, antioxidant) and tolerability suggest it could help protect normal colon during pelvic RT.	Short-term; no survival follow-up; surgery not RT-based; dosage bioavailability issues.	Conduct peri-RT supplementation with follow-up on GI toxicity.
NCT02577393 EGCG	Phase II	Lung Cancer	40	Oral EGCG daily	Decreased inflammatory markers; improved lung function in chemo-treated patients.	In a phase-2, three-arm RCT of lung-cancer patients receiving thoracic RT, oral EGCG significantly lowered the maximum grade and symptom indices of acute radiation-induced esophagitis vs. standard care–evidence of normal-tissue radioprotection during thoracic RT (hence possible lung radioprotection).	Adjunctive to chemo, not RT; small sample, lack of tumor-specific markers or fibrosis data.	Apply in thoracic RT with fibrosis markers and lung function tests.
NCT02289833 Maytansine ADC	Phase II	Metastatic HER2+ Cancers	60	ADC dosing every 3 weeks	Partial response rates in refractory HER2+ tumors.	Phase II trial of ado-trastuzumab emtansine (T-DM1) in HER2-IHC–positive NSCLC showed responses mainly in IHC 3+ tumors; since T-DM1 delivers the microtubule poison DM1 (a class that can radiosensitize via G2/M arrest), supporting a potential radiosensitizer trait in HER2+ cancers via microtubule disruption.	Not a pure phytochemical; systemic toxicity; no RT combination studied.	Explore low-dose ADCs with RT to balance efficacy/toxicity.
NCT02553187 Kanglaite (coix seed extract)	Phase II	Pancreatic Cancer	50	IV infusion cycles	Improved tolerance to chemo; possible survival benefit.	This trial tested Kanglaite injection for cancer cachexia in advanced NSCLC/colorectal/pancreatic cancer and explicitly excluded patients receiving radiation therapy. Evidence for supportive-care use in cancer cachexia, i.e., evaluating Kanglaite to stabilize/improve weight, appetite, and quality of life and to document safety in advanced solid tumors.	Chemo-adjunct only; no radiation context; pharmacodynamics not aligned with RT scheduling.	Combine with chemoradiation regimens; assess GI toxicity.
NCT00099190 Cryptophycin 52 analog	Phase II	NSCLC, ovarian cancer	80	IV infusion per 3-week cycle	Anti-tumor activity but unacceptable neurotoxicity at higher doses.	This study combined ARQ-501 with docetaxel, a microtubule-stabilizing agent that causes G2/M arrest at sub-cytotoxic doses–an established radiosensitization window–supporting the idea that low-dose microtubule damage could enhance RT efficacy.	Severe neurotoxicity; narrow therapeutic window; RT not tested.	Microdosing + targeted RT delivery to reduce systemic exposure.

Study Methodology

A literature search was carried out with the help of Google Scholar and PubMed to obtain studies on phytochemicals having possible functions in radiation therapy. The search included recent preclinical and clinical research articles.

Clinical trial data extraction

Data for the tables were retrieved from ClinicalTrials.gov and NCBI, considering the most frequent phytochemicals studied in cancer research. The selection was based on the frequency of studies available in recent literature. The individual phytochemicals and their respective study numbers were as follows: curcumin, 85 studies; resveratrol, 17 studies; quercetin, 21 studies; lycopene, 23 studies; capsaicin, 19 studies; EGCG (epigallocatechin gallate), 37 studies; genistein, 29 studies; omega-3 fatty acids, 52 studies; white button mushroom extract, 3 studies; sulforaphane, 16 studies.

Data sources and search strategy

We first conducted a literature search through Google Scholar and/or PubMed. Clinical-trial records were retrieved from ClinicalTrials.gov (and aligned sources where available) using phytochemical-specific queries in the format “[phytochemical name] in cancer therapy]”. Data for [Table 1] were retrieved from the NCBI database using the search term “phytochemicals in cancer therapy”. Studies were included if they (i) reported experimental or clinical evidence of anticancer effects of a specific phytochemical, (ii) described at least one molecular or cellular mechanism of action, and (iii) were published in peer-reviewed journals. To ensure diversity and avoid bias toward any single cancer type or phytochemical, records were selected using a random sampling approach from the pool of eligible studies. This approach allowed [Table 1] to serve as a broad, non-frequency-weighted reference of phytochemicals and their mechanistic roles in cancer therapy. Similarly, for [Table 2], a targeted search was conducted in relevant biomedical databases using the query “phytochemical (specific name) in cancer therapy” for each phytochemical of interest. This search yielded a total of 302 records. For each phytochemical, the three most frequently reported cancer types were identified and included in the table. Two exceptions applied: (i) lycopene: only one cancer type (prostate cancer) was reported frequently enough to be included, making frequency ranking unnecessary; and (ii) white button mushroom extract: only three records were found in total, so all were included without frequency selection. This frequency-based approach ensures [Table 2] reflects the relative research emphasis for each phytochemical in specific cancer contexts for translational relevance and research priorities.

Figure preparation

All figures were designed and illustrated using Biorender software (created in BioRender. Dweh, T. (2025) https://BioRender.com/iy869o3) to visually represent the mechanisms, while the figures having the structures of phytochemicals were retrieved from PubChem (https://pubchem.ncbi.nlm.nih.gov/) and ChemDraw.

Current Status of Phytochemicals in Radiation Therapy

Studies have shown that phytochemicals, categorized into phenolics, carotenoids, organosulfur compounds, nitrogen-containing compounds, and alkaloids, can impact various pathways [15]. Phytoestrogens (compounds having structural and functional resemblance to estrogen), such as equal and enterolactone, have been found to reduce breast cancer risk by inhibiting autophagy (cellular self-digestion process) and increasing susceptibility of cells or tissues to radiation-induced damage (radiosensitivity). Phytochemicals like apigenin can also scavenge free radicals and activate the NF-E2-related factor 2 (Nrf2) signaling pathway, which is a regulator of antioxidant response and redox homeostasis [16]. Through this mechanism, antioxidant enzymes are activated, inducing stress defense molecules. For example, Nrf2, a transcription factor, promotes the expression of antioxidant genes, leading to the sequestration of free radicals. The Nrf2 pathway has also been regulated by other phytochemicals, resveratrol, curcumin, lycopene, etc., in much the same way as apigenin, indicating a similar mode of action [17].

Similarly, curcumin has been found to decrease reactive oxygen species (ROS) production and lipid peroxidation, leading to DNA repair, cell cycle regulation, and apoptosis. Phytochemicals, particularly those that modulate ROS and autophagy, have anticancer effects with minimal side effects [18]. These phytochemicals serve as radioprotectors, shielding cells from ionizing radiation, and radiosensitizers, increasing cell sensitivity to radiation [19], [20] as shown in [Fig. 1]. These mechanisms can interact to affect cancer development through various pathways.

Fig. 1 Mechanisms of Phytochemicals in Radiation-Induced Fibrosis via CTGF Pathway Activation. a Anti-inflammatory Defense: Phytochemicals (indicated in red) suppress pro-inflammatory cytokines and chemokines, thereby mitigating the inflammatory response associated with radiation-induced fibrosis. b Antioxidant Response: Phytochemicals (indicated in black) reduce reactive oxygen species (ROS) by generating oppositely charged particles. This antioxidant activity inhibits extracellular matrix (ECM) deposition, leading to the downregulation of proteins and genes that promote aberrant cell proliferation and metastasis. c Inhibition of the TGF-β Pathway: Phytochemicals (indicated in green) inhibit TGF-β signaling by introducing phosphate groups that activate downstream proteins such as Smad1 and Smad2, key regulators in fibrosis pathways. (i) Epigallocatechin-3-gallate (EGCG) inhibits ATM protein activation, preventing the activation of the p53 survival pathway. (ii) Phytochemicals such as curcumin, resveratrol, and genistein can also bind to cytoplasmic ligands, triggering Notch receptor activation and inducing damage to the plasma membrane. Figure created in BioRender. Dweh, T. (2025) https://BioRender.com/iy869o3 [rerif].

Phytochemicals as Radioprotectors

Radioprotectors are those phytochemicals that neutralize reactive free radicals, protecting against oxidative stress caused by ionizing radiation, and possess antioxidant properties. They can mitigate the harmful effects of ionizing radiation on normal cells while preserving its therapeutic effects on cancer cells [21]. Radioprotectors can also influence cell cycle control points, promoting a pause in cell division, aiding in DNA repair, and halting the spread of harmed cells. Indole-3-carbinol, a naturally occurring phytochemical found in vegetables like broccoli, has been shown to trigger cell cycle pause and shield against radiation-induced DNA damage [22].

Radioprotectors can modulate signaling pathways involved in radiation-induced stress responses, such as the Nrf2 pathway, which manages the production of protective enzymes and detoxification proteins [23]. Curcumin, a natural compound found in some plants, has been proven to trigger this Nrf2 pathway and protect against radiation-caused genetic damage. Similarly, many phytochemicals control cancer cell growth and survival by inducing cell cycle arrest and promoting apoptosis, targeting signaling pathways in cell cycle regulation, apoptosis, and DNA damage response [24].

Phytochemicals as Radiosensitizers

Radiosensitizers refer to those phytochemicals that boost the effectiveness of radiation therapy by making cancer cells more responsive to its effects. They achieve this by disrupting DNA repair, influencing cell death pathways, and modifying the tumor microenvironment, thereby increasing the vulnerability of cancer cells to radiation damage [25]. For example, resveratrol, a natural compound with antioxidant, anti-inflammatory, and antiproliferative properties, enhances the sensitivity of cervical cancer cells to radiation therapy. Its effects are mediated through pathways like p53 activation and modulation of pro-apoptotic factors [26], [27].

Phytochemicals can enhance radiation therapy by sensitizing cancer cells to DNA damage and cell death. They target pathways like ATM/TP53, MARK, and NF-kB, initiating a cascade of events leading to cell cycle arrest and apoptosis [28]. During the arrest, phytochemicals disrupt normal progression, making cancer vulnerable to radiation therapy effects. Some phytochemicals can counter-react by influencing the activation of pro-apoptotic signals by expressing B-cell lymphoma 2 (Bcl-2) family members (regulatory proteins that control apoptosis), caspases, and apoptotic receptors. First, caspase-3 activation triggers apoptosis by inducing DNA fragmentation, then nuclear condensation and membrane blebbing, ultimately leading to cancer cell death [29], [30].

Many phytochemicals have been shown to affect critical cell survival pathways, such as the PI3K/Akt pathway, which is essential for controlling cell growth, metabolism, survival, and resistance to programmed cell death. Blocking PI3K prevents Akt activation, disrupting downstream signaling events and blocking FOXO (Forkhead box O) transcription factors, which are also a family of tumor suppressor proteins that regulate several cellular processes. This results in cell survival and apoptosis regulation, inhibiting tumor growth. Phytochemicals can also inhibit mTOR (mechanistic target of rapamycin) activation by blocking Akt-mediated phosphorylation or directly targeting it ([Fig. 2]) [31], [32].

Fig. 2 Schematic Contrasting Tumor vs. Normal-Tissue Contexts. In tumor cells, representative agents (e.g., genistein, quercetin, and curcumin) inhibit PI3K/Akt phosphorylation, downregulate mTOR/Bcl-2, impair DNA-damage repair signaling (e.g., ATM/RAD51 axis), and tip signaling toward apoptosis–thereby enhancing radiosensitization. In normal tissues, controlled PI3K/Akt activation (e.g., by EGCG) promotes Nrf2 nuclear translocation and antioxidant gene induction (HO-1, GPx, SOD1), limiting ROS injury. The center layer highlights clinical moderators–tumor type, microenvironment, radiation dose/fractionation, and combinations that determine whether a compound functions as a radiosensitizer or radioprotector. Crosstalk with TGF-β/Smad and non-canonical MAPK pathways links to fibrosis control via CTGF down-modulation and restored MMP/TIMP balance. Figure created in BioRender. Dweh, T. (2025) https://BioRender.com/iy869o3 [rerif].

Context-Dependent Effects of Phytochemicals in Radiation Therapy

Phytochemicals have an intricate role to play in radiation therapy, acting either as radiosensitizers or as radioprotectors, depending on variables like the type of tumor, dose of radiation, fractionation regimen of radiation, and treatment protocol. They play a dual function since they are able to modulate oxidative stress, DNA repair processes, inflammatory responses, and cell cycle functions ([Fig. 3]).

Fig. 3 Phytochemicals in Cancer Therapy–Structures and Mechanisms of Action. This figure presents well-characterized phytochemicals (sourced from PubChem and ChemDraw) commonly utilized in cancer therapy, alongside their chemical structures and modes of action. Key compounds such as curcumin, resveratrol, epigallocatechin-3-gallate (EGCG), genistein, and others are illustrated. These phytochemicals are known to induce apoptosis, alleviate oxidative stress, and inhibit pro-survival signaling pathways (e.g., PI3K/AKT, NF-κB) and to target critical regulatory molecules such as ATM, RAD51, Bcl-2, and caspases. Collectively, these compounds have demonstrated dual roles as both radio-protectors and radio-sensitizers, contributing to improved efficacy in cancer radiotherapy. Figure created in BioRender. Dweh, T. (2025) https://BioRender.com/iy869o3 [rerif].

Knowledge of these mechanisms is essential for the optimal clinical use of phytochemicals in radiation therapy. Their action is strongly modulated by tumor type, cellular microenvironment, radiation dose, and combination treatment approaches. For example, genistein, a flavonoid from soy, is a radioprotector in normal tissues through the mitigation of oxidative stress and augmentation of DNA repair, but is a radiosensitizer in tumor cells by inhibiting DNA repair and inducing apoptosis. Likewise, quercetin guards normal cells against radiation-induced oxidative stress by modulating NRF2 and PI3K/Akt pathways, sensitizing cancer cells by inhibiting pro-survival signals [33]. The interplay between PI3K/Akt, Nrf2/ARE, and TGF-β signaling is central to the dual role of phytochemicals in radiation therapy. In tumor cells, phytochemicals such as genistein, quercetin, and curcumin suppress PI3K/Akt phosphorylation, downregulate mTOR and Bcl-2, and activate pro-apoptotic mediators, sensitizing cancer cells to ionizing radiation. Conversely, in normal cells, controlled activation of PI3K/Akt by compounds like EGCG can facilitate Nrf2 nuclear translocation, enhancing antioxidant gene expression (HO-1, GPx, and SOD1) and mitigating ROS-induced injury ([Fig. 4]). This duality is further exemplified in the context of radiation-induced fibrosis, where phytochemicals inhibit TGF-β-mediated Smad2/3 and non-canonical MAPK pathways, downregulate CTGF, and restore MMP/TIMP balance, thereby preventing excessive ECM deposition. The crosstalk among these pathways underscores the necessity of dose optimization and treatment scheduling to maximize tumor radiosensitization while preserving normal tissue function.

Fig. 4 Diagram Summarizing How Outcome Flips With Dose and Treatment Context. Curcumin selectively radiosensitizes tumors by suppressing NF-κB, STAT3, and HIF-1α while protecting normal tissue from oxidative damage; at lower radiation doses, its antioxidant activity may blunt tumor kill. Lycopene protects at low exposure but shifts toward pro-apoptotic, anti-proliferative effects at higher exposure. EGCG can both enhance tumor radiosensitivity (via DNA-repair inhibition) and protect normal tissue depending on regimen and pairing with other therapies. The figure emphasizes the need for individualized strategies that integrate tumor biology with radiation schedules and combination therapy. Figure created in BioRender. Dweh, T. (2025) https://BioRender.com/iy869o3 [rerif].

Curcumin with antioxidant and anti-inflammatory activity selectively sensitizes tumors to radiation by inhibiting NF-κB, STAT3, and HIF-1α pathways, thus promoting a therapeutic response while protecting normal tissue from oxidative damage [34]. However, at lower radiation doses, its antioxidant activity might counteract tumor cell death, potentially diminishing treatment efficacy. Lycopene exhibits similar dose-specific behavior–protecting normal cells at low radiation exposure but promoting apoptosis and inhibiting cancer cell proliferation at higher doses [35]. Moreover, the efficacy of phytochemicals as radiosensitizers or radioprotectors may be contingent on their employment in conjunction with chemotherapy, immunotherapy, or targeted therapies. For instance, epigallocatechin gallate (EGCG) has been found to enhance tumor radiosensitivity through the inhibition of DNA repair but, at the same time, provides protection to normal tissues in certain situations, highlighting its dual function based on therapeutic parameters. In concert, these results identify the necessity for individualized strategies that take into account tumor biology, radiation schedules, and combination strategies to fully realize the therapeutic potential of phytochemicals in cancer radiotherapy.

Radiation-Induced Fibrosis (RIF) and the Corresponding Mechanistic Insight

RIF is a multifactorial condition arising from impaired wound healing following radiation exposure. It is marked by persistent inflammation, oxidative stress, and metabolic alterations, leading to the continuous activation of myofibroblast–cells derived from fibroblast, epithelial and endothelial cells through epithelial-to-mesenchymal transition (EMT). These myofibroblasts, characterized by α-SMA expression, produce excessive collagen and extracellular matrix (ECM), driving fibrotic tissue buildup. Normally, myofibroblasts undergo apoptosis after tissue repair; however, in RIF, chronic inflammation maintains their survival and activity. Key cytokines and growth factors such as TGF-β, CTGF, PDGF, and various interleukins (IL-6, IL-2) secreted by immune cells–especially polarized M2 macrophages–orchestrate this process. The crosstalk between canonical (Smad) and non-canonical (MAPK, ERK, p38) signaling pathways further amplifies fibroblast activation and ECM deposition. Together, these events lead to progressive tissue fibrosis and functional impairment, as illustrated in [Fig. 5].

Fig. 5 Immune Cell Dynamics and Fibroblast Activation in Radiation-Induced Injury. Following radiation injury, immune cells including lymphocytes, neutrophils, and monocytes are recruited to the damaged site. Monocytes differentiate into macrophages, which subsequently polarize into the M2 phenotype. These M2 macrophages secrete platelet-derived growth factor (PDGF), promoting the migration of fibroblasts derived from surrounding stromal cells or circulating mesenchymal stem cells to the site of injury. Additionally, transforming growth factor-beta (TGF-β) released by M2 macrophages drives epithelial-mesenchymal transition (EMT), facilitating the differentiation of pro-myofibroblast intermediates into stromal fibroblasts and mature circulating fibrocytes, ultimately contributing to fibrotic tissue remodeling. Figure created in BioRender. Dweh, T. (2025) https://BioRender.com/iy869o3 [rerif].

TGF-β, a protein, secretes Treg cells that regulate fibrosis through its isoforms TGF-β1, TGF-β2, and TGF-β3. These cells mainly regulate fibrogenesis and the transformation of fibroblasts into myofibroblasts [36]. The TGF-β/LAP/LTBP complex, the weakest of TGF-β1, is activated in the presence of fibrogenic enzymes and matrix metalloproteinases. Other TGF-β-related pathways, such as PI3K/Akt, MAPK, and AMPK, also play a role in fibrosis. Inhibition of the P38/MAPK/AKT signaling pathway reduces radiation-induced myofibroblast transformation [37]. TGF-β can activate all three MAPK signaling pathways, including p38, MAPK, ERK, and the c-linker N-terminal pathway [38].

ECM proteins are important for tissue architecture, yet fibrosis arises when their regulation goes wrong, such as in radiation-induced fibrosis. This takes place following upregulation of CTGF, a connective tissue growth factor, which is induced following radiation exposure, macrophage activation, release of pro-inflammatory cytokines, activation of fibroblasts, CTGF upregulation and signaling, and ECM remodeling. These cytokines recruit and stimulate fibroblasts, and both myofibroblasts and CTGF have the same action [39]. CTGF is a profibrotic factor as it binds to the receptors of fibroblasts and myofibroblasts, initiating downstream signaling pathways and resulting in enhanced ECM. ECM components such as collagen, fibronectin, and elastin are involved in the development of fibrosis.

CTGF is responsible for radiation-induced lung fibrosis and toxicity. Radiation exposure initiates an inflammatory response, leading to edema and an influx of leukocytes, such as macrophages. This inflammation subsides after a few weeks, leading to a subsequent phase 18 – 20 weeks after irradiation, with a higher peak of leukocyte infiltration, especially in macrophages. These macrophages are involved in tissue repair and remodeling by releasing factors like CTGF. CTGF is upregulated in response to radiation, activating fibroblasts and depositing extracellular matrix components [40], [41]. FG-3019, a monoclonal antibody, blocks CTGF expression of transcripts associated with mesenchymal cell-type inclusion ECM remodeling, indicating its association with RIF processes [42] as seen in [Fig. 4]. This process leads to fibroblasts being continuously activated and proliferated, ultimately leading to radiation-induced lung fibrosis.

Two phytochemicals that are capable of efficiently controlling the TGF-β signaling pathway are curcumin and emodin. They lower the expression of common Smads, R-Smads, and TGF-β receptor II, which combine to create active transcriptional complexes that regulate the expression of target genes [43]. This guarantees that the TGF-β signal is adequately transmitted to the nucleus; by suppressing downstream effectors such as Cyclin D1, P21, and NIMA 1, curcumin and emodin cause mesenchymal markers to be downregulated, which prevents cell invasion and migration. Additionally, curcumin and emodin inhibit cell viability in SiHa and HeLa cells by causing G2/M arrest in SiHa cells and partial arrest in emodin cells. However, TGF-β negates this effect, increasing apoptosis in HeLa cells. This is achieved by suppressing β-catenin expression, a Wnt pathway component, through downregulating Bcl-2, facilitated by miR-34a [44].

Studies have shown that phytochemicals can inhibit CTGF expression and attenuate fibrosis in various tissues, including the liver and kidney. Among these are resveratrol, curcumin, epigallocatechin-3-gallate (EGCG), etc.; resveratrol is sourced from grapes, berries, and peanuts, and curcumin exerts its anti-fibrotic effects through multiple mechanisms, including the inhibition of TGF-β signaling, which is known to upregulate CTGF expression [45]. TGF-β signaling is suppressed by preventing the activation and phosphorylation of Smad proteins, downstream effectors of TGF-β signaling, and, after inhibiting the activation of Smad, resveratrol and curcumin inhibit the transcriptional activation of CTGF and fibrotic genes [46]. EGCG, a green tea polyphenol, has been shown to suppress the production of CTGF and reduce fibrosis in various organs, such as the kidney and liver. It acts as an antioxidant that quenches reactive oxygen species (ROS) and reduces oxidative stress, which promotes inflammation and deposition of the extracellular matrix (ECM) and causes fibrosis to develop [47], [48]. In addition, EGCG suppresses chemokine and pro-inflammatory cytokine production, both of which are crucial for fibrotic tissue formation. Resveratrol, the most common polyphenol in green tea, is able to regulate the MMP-to-TIMP ratio, preventing fibrosis and over-ECM deposition ([Fig. 6]) [49], [50].

Fig. 6 TGF-β–Mediated Fibrosis via Smad-Dependent and Smad-Independent Pathways. This illustration depicts the dual signaling mechanisms of Transforming Growth Factor-β (TGF-β) in promoting fibroblast activation and fibrosis. Upon ligand binding, the TGF-β receptor becomes phosphorylated, initiating downstream signaling cascades. In the canonical Smad-dependent pathway, the activated receptor complex phosphorylates Smad2 and Smad3, which then associate with Smad4. The resulting Smad complex translocates into the nucleus to regulate transcription of genes responsible for fibroblast activation, collagen synthesis, and extracellular matrix (ECM) deposition. In parallel, Smad-independent pathways may also contribute to these processes through alternative signaling routes. Together, these pathways sustain fibroblast activity and ECM accumulation, key features of radiation-induced fibrosis (RIF). Figure created in BioRender. Dweh, T. (2025) https://BioRender.com/iy869o3 [rerif].

Phytochemical Interventions for Fibrosis Mitigation via YAP/TAZ Pathway

The activation of the yes-associated protein and transcriptional co-activator with PDZ-binding motif (YAP/TAZ)–a key effector of the Hippo signaling pathway that regulates cell proliferation, differentiation, and tissue regeneration through radiation–has been studied in various cancers, including breast cancer, lung, pancreatic, and colorectal. A study on lung cancer identified that radiation activates a pathway referred to as Hippo, activating YAP/TAZ and migrating into the nucleus of the cell [51]. The protein assists cells in survival and growth and makes them more resistant to radiation by amplifying DNA repair gene expression. YAP/TAZ also stimulates cyclin D1 and evokes radio-resistance through suppressing cell cycle inhibitors. It affects apoptosis and cell survival by increasing anti-apoptotic genes like Bcl-2 and survivin and decreasing proapoptotic genes like Bax and caspase-3. Adding phosphate groups to Akt (protein kinase B (PKB)) enhances it (Akt), making cells more viable and less susceptible to apoptotic processes similar to cell damage [52].

Resveratrol and curcumin can inhibit nuclear translocation, which triggers YAP/TAZ, by disrupting its transcriptional coactivators like TEAD (transcriptional enhancer factor domain) proteins–a group of transcription factors that regulate cellular processes and are primary nuclear effectors of the Hippo-YAP/TAZ pathways [53]. They can also modulate water flux signaling by inhibiting PI3K/Akt signaling. Phytochemicals such as genistein and isoflavones of soy may influence the Hippo pathway, the YAP/Master regulator of TAZ activities that controls cell growth, tissue homeostasis, and regulation of organ size. Excessive downstream effectors, e.g., the LATS (large tumor suppressor) kinase, may facilitate cancer [54], [55]. Genistein can aid these kinases by adding phosphate groups, leading to cytoplasmic retention and inhibiting transcriptional activities. Genistein can also regulate the activity of genes related to the Hippo pathway and YAP/TAZ to promote fibrotic responses, such as increasing the mammalian Ste20-like kinase 1(MST1), an activator of LATS1/2 kinases, causing the phosphorylation and inhibition of YAP/TAZ, which initiates the Hippo pathway, leading to uncontrolled tumor growth.

Potential Phytochemicals in Cancer Therapy

While numerous phytochemicals have been extensively explored for their anticancer properties, a vast reservoir of bioactive compounds remains underutilized. Several natural compounds, primarily studied for their therapeutic effects in non-cancerous diseases like pulmonary fibrosis and acute lung injury, exhibit promising mechanisms that could be harnessed for cancer therapy. These overlooked phytochemicals possess potent antioxidant, anti-inflammatory, and antifibrotic properties–key attributes that could redefine cancer treatment strategies ([Fig. 7]) [56].

Fig. 7 Chemical Structures of Phytochemical Drug Candidates for Cancer Therapy. This figure displays the 2D molecular structures of selected phytochemical compounds retrieved from PubChem, identified as potential drug candidates for cancer therapy. These compounds, including curcumin, resveratrol, epigallocatechin-3-gallate (EGCG), genistein, and others, are widely studied for their anti-cancer properties, such as apoptosis induction, oxidative stress regulation, and modulation of key signaling pathways. Their structural diversity underscores their potential for multi-targeted therapeutic applications in cancer treatment. Figure created in PubChem followed by BioRender. Dweh, T. (2025) https://BioRender.com/iy869o3 [rerif].

For instance, astilbin, known for its role in reducing oxidative stress and inflammation in pulmonary fibrosis, could potentially suppress tumor progression by targeting the hedgehog signaling pathway and TGF-β/Smad cascade. Likewise, juglanin, anti-inflammatory in acute lung injury, might be repurposed to regulate the tumor microenvironment by suppressing the NF-κB and TGF-β1/Smad3 pathways.

Another potential candidate, puerarin, well known for its antifibrotic activity in pulmonary hypertension, can reverse fibrosis caused by radiation in cancer treatment through modulating HIF-1α and TGF-β signaling. Similarly, isorhamnetin, which has been mainly researched for antioxidative and anti-inflammatory activity in fibrosis, might increase the radiosensitivity of tumors through ER stress modulation and EMT inhibition.

The function of flavonoids epicatechin and kaempferol in pulmonary fibrosis also solidifies their promise in oncology. The capacity of epicatechin to regulate oxidative stress pathways–of paramount importance for tumor resistance–implies its therapeutic significance in the conquest of radiation resistance. Kaempferolʼs influence on autophagy and fibrosis regulation in lung disease could translate even more directly into cancer cell reprogramming and survival regulation. Additionally, Murraya koenigii and its key phytochemical, mahanine, have demonstrated significant potential as anticancer agents by targeting multiple cellular signaling pathways. MK contains over 80 alkaloids, flavonoids, and terpenoids, several of which–such as mahanine, girinimbine, koenimbine, and quercetin–exhibit significant anticancer effects (the structures of the compounds are shown in the above figure). Mahanine, in particular, demonstrated apoptosis induction via ROS generation, inhibition of AKT/mTOR, STAT3, and HSP90 pathways, DNA minor groove binding, and epigenetic modulation (e.g., DNMT inhibition and RASSF1A re-expression). In vivo, mahanine reduced tumor volume across xenograft models with minimal toxicity [57].

Limitations, Clinical Relevance, and Future Road Map

In spite of the promising future of phytochemicals in radiation therapy, some key limitations need to be overcome before their universal application in the clinic. Such limitations are bioavailability, absence of dosage standardization, and patient-specific toxicity, and these can influence treatment efficacy to a large extent. A critical bottleneck in translating phytochemicals from bench to bedside lies in their poor bioavailability, driven by low aqueous solubility, instability under physiological conditions, extensive first-pass metabolism, and rapid systemic clearance. Curcumin, for instance, exhibits an oral bioavailability of < 1% due to poor absorption and extensive glucuronidation, while resveratrol undergoes > 75% first-pass metabolism, yielding plasma levels insufficient for sustained radiosensitizing or radioprotective effects [58], [59]. EGCGʼs bioavailability is similarly compromised by pH-dependent degradation and efflux via P-glycoprotein transporters.

Patient-specific variability further compounds this problem: genetic polymorphisms in metabolizing enzymes (e.g., UGT1A1 for curcumin, COMT for catechins) gut microbiota composition, and diet–drug interactions can shift pharmacokinetics unpredictably, making “one-size-fits-all” dosing impractical [60]. Moreover, for radiation oncology, bioavailability optimization is not simply about increasing systemic exposure–it must ensure temporal and spatial alignment with radiation delivery. This requires synchronization of peak phytochemical plasma/tumor concentrations with RT fractions, which can be achieved through innovative delivery platforms (e.g., RT-responsive nanoparticles that release payload upon exposure to ionizing radiation-induced ROS) [61]. Such integration of pharmacokinetics with radiation physics could enhance the therapeutic index, ensuring maximal tumor radiosensitization and minimal normal tissue.

Overcoming the bioavailability limitations of phytochemicals is crucial to fully harness their therapeutic potential in radiation oncology. A major challenge lies in dosage standardization and treatment optimization, as preclinical and clinical studies have reported inconsistent outcomes–low doses of certain phytochemicals often provide radioprotective effects, while higher doses can act as radiosensitizers. For instance, lycopene has been shown to protect normal tissues at low concentrations but induce apoptosis at higher levels. Moreover, the route of administration–whether oral, intravenous, or nano-formulated–significantly influences efficacy, emphasizing the need for standardized clinical protocols. Patient-specific responses further complicate treatment, as genetic, metabolic, and dietary factors affect how individuals metabolize and respond to phytochemicals. Some compounds also interact with cytochrome P450 enzymes, altering drug metabolism and therapeutic outcomes, which calls for precision oncology approaches to personalize treatment.

Altogether, the present review highlights several innovative strategies, illustrated in [Fig. 8], that are emerging to overcome these barriers. Nanotechnology-enabled delivery systems, such as polymeric nanoparticles, liposomes, and solid lipid nanoparticles, have markedly improved curcuminʼs C_max and half-life, with certain formulations achieving 5 – 10-fold higher tumor accumulation and enhanced radiosensitization in xenograft models; similarly, liposomal resveratrol has demonstrated threefold greater plasma exposure and reduced hepatic metabolism. Prodrug design approaches, including esterification or phospholipid conjugation, have been employed to develop prodrugs of EGCG and quercetin with enhanced stability and passive permeability. Co-administration with bioenhancers, such as piperine, has shown dramatic effects–increasing curcuminʼs bioavailability by 2000% in human trials through inhibition of glucuronidation (Shoba et al., 1998)–and similar strategies with quercetin have yielded synergistic inhibition of CYP3A4 and P-gp efflux pumps. Targeted delivery systems, including folate-, transferrin-, or antibody-decorated nanoparticles, enable selective tumor accumulation, raising intratumoral concentrations while minimizing systemic exposure–an important consideration in maximizing tumor radiosensitization while protecting normal tissues. Furthermore, personalized pharmacokinetic modeling, integrating genomic and metabolomic profiling with physiologically based pharmacokinetic (PBPK) simulations, offers the potential to predict optimal dosing schedules tailored to individual enzyme polymorphisms, microbiome signatures, and radiotherapy-specific physiological changes.

Fig. 8 Concept Map Linking Major Clinical Obstacles to Targeted Solutions. Barriers: poor bioavailability due to low solubility, chemical instability, first-pass metabolism, and rapid systemic clearance (for example, curcumin with less than 1% oral bioavailability; resveratrol with more than 75% undergoing first-pass metabolism), active efflux by membrane transporters, and large inter-patient variability influenced by genetic polymorphisms such as UGT1A1 and COMT, as well as differences in microbiome composition and dietary habits. Additional challenges include the absence of standardized dosing protocols and the difficulty in synchronizing phytochemical exposure with radiotherapy fractionation schedules. Strategies: application of nanotechnology-based delivery systems such as polymeric nanoparticles, liposomes, and solid-lipid carriers to enhance tumor accumulation and radiosensitization (for example, liposomal resveratrol increasing plasma exposure); prodrug design approaches using compounds such as EGCG or quercetin; use of bioavailability enhancers such as piperine, which can increase curcumin bioavailability by approximately 2000 percent; functionalization of nanoparticles with targeting ligands such as folate, transferrin, or monoclonal antibodies; and implementation of personalized physiologically based pharmacokinetic (PBPK) modeling to align peak intratumoral drug levels with planned radiotherapy fractions, including systems triggered by radiotherapy or reactive oxygen species for controlled release. Figure created in BioRender. Dweh, T. (2025) https://BioRender.com/iy869o3 [rerif].

Discussion and Conclusion

This study integrates clinical-trial mapping, mechanistic synthesis, and translational challenges to provide a comprehensive evaluation of phytochemicals in cancer therapy, with a particular focus on their dual potential as radiosensitizers and radioprotectors. [Tables 1] and [2] map both the diversity of phytochemicals under investigation and the cancer types in which they are most frequently studied, while [Fig. 2], [Fig. 4], and [Fig. 8] illustrate context-dependence, dose/regimen influence, and translational barriers.

The current clinical evidence base is dominated by early phase studies with small sample sizes, heterogeneous endpoints, and inconsistent reporting of formulation, dosing, and pharmacokinetic parameters. While strong mechanistic support exists for tumor radiosensitization–through inhibition of the NF-κB, STAT3, and HIF-1α pathways, and impairment of DNA repair via ATM/RAD51–normal tissue radioprotection is equally well-substantiated via Nrf2-mediated antioxidant responses. However, most trials do not integrate pharmacokinetic monitoring with radiotherapy fraction timing, and normal-tissue protection endpoints are inconsistently assessed, limiting the ability to quantify the true therapeutic ratio.

The dual action of phytochemicals is influenced by tumor–normal tissue context, radiation dose, and treatment regimen ([Fig. 2] and [Fig. 4]). The radiosensitization window typically coincides with peak intratumoral exposure shortly before radiation delivery, whereas radioprotection benefits from earlier dosing that allows transcriptional activation of antioxidant pathways. Beyond the tumor cell, critical but underrepresented mechanisms–such as modulation of immune–radiotherapy crosstalk (STING activation, antigen presentation, and macrophage/MDSC reprogramming), hypoxia adaptation, and stromal TGF-β/CTGF-mediated fibrosis–represent important opportunities for further exploration. [Fig. 8] highlights three major barriers: poor bioavailability, pharmacogenetic and microbiome-driven variability, and lack of standardized dosing or exposure anchoring. Addressing these requires the following: 1. exposure anchoring: reporting C_max/AUC and, where possible, intratumoral concentrations; 2. target engagement confirmation: biomarker panels such as γ-H2AX for DNA damage, NF-κB/STAT3 suppression, and Nrf2 target induction; 3. RT-aligned clinical endpoints: simultaneous measurement of tumor control and normal-tissue toxicity using CTCAE and PRO-CTCAE tools.

Innovative approaches include the following: PBPK model-guided scheduling to align drug peaks with intended radiosensitization or radioprotection windows; nanotechnology-enabled, targeted, or ROS/pH-triggered delivery systems; biomarker-enriched trial enrolment based on NFE2L2/KEAP1 status, DNA-repair defects, hypoxia imaging, and transporter polymorphisms; and integration with immunotherapy to exploit phytochemical-driven immune modulation. It is worth adding that potential interactions with cytochrome P450 enzymes and P-glycoprotein transporters and antioxidant interference with chemoradiation should be explicitly addressed in the trial design. Supplement co-use during active treatment should be carefully monitored or restricted.

Overall, phytochemicals offer a unique opportunity to enhance the therapeutic ratio of radiotherapy by selectively radiosensitizing tumors and protecting normal tissues, but this promise remains under-realized due to translational and methodological gaps. This manuscript provides both a critical appraisal of current evidence and a clear innovation pathway–combining exposure-guided scheduling, biomarker integration, targeted delivery, and precision patient selection–to advance these agents from supportive theory to clinically validated practice. By linking mechanistic insight with clinical trial strategy, the framework outlined here can guide the next generation of rigorously designed, biomarker-driven studies that maximize benefit, minimize harm, and bring phytochemical–radiotherapy combinations into mainstream oncologic care.

Contributorsʼ Statement

Conceptualization, investigation, data collection, and initial drafting: TJD, MT, and DD. Critical revisions and supervision and contributed to the overall structure and critical review: SKS. Supervision, conceptual support, and expert guidance: NCT. All authors read and approved the final version of the manuscript.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgements

The authors want to acknowledge the Assam Down Town University for the laboratory infrastructure and the seed money grant with memo No. AdtUlN2024-251295. The authors would like to acknowledge the use of AI-based tools such as OpenAIʼs ChatGPT for assistance in rephrasing certain sentences to enhance clarity and readability. However, the authors affirm that all data and scientific content presented in this review article were generated independently and not produced by AI tools.

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