Diterpenic compounds with selective antiproliferative activity in multidrug resistant cancer cells

The failure of chemotherapeutics in cancer is mainly imputed to multidrug resistance (MDR). Among several proposed approaches to overcome MDR, the modulation of P-glycoprotein (Pgp) is the most highlighted [1]. Another valuable strategy is to take advantage of the collateral sensitivity effect, where some compounds may selectively exert a more pronounced cytotoxicity on cells with MDR phenotype than in the parental ones [1]. Macrocyclic diterpenes isolated from Euphorbia species, have been recognized as potent Pgp modulators and as having a collateral sensitivity effect on MDR cell variants [2]. Our main goal is to explore these two approaches, since tackling more than one MDR mechanism simultaneously might be a solution to control MDR in its complexity. The fractionation of the methanol extract of the aerial parts of E. piscatoria led to the isolation of a macrocyclic diterpene that allowed to build a small library of derivatives [3]. In this work, eleven compounds were evaluated for their potential collateral sensitivity effect on nine cell lines, gastric, pancreatic and colon cancer cell models (drug sensitive and drug resistant sublines), using the SRB assay. Most of the derivatives exhibited significant collateral sensitivity effect towards the MDR gastric cell line (with Pgp overexpression) and the MDR colon cells. The most significant results were obtained with a benzoyl derivative that demonstrated ability to target different cellular contexts with concomitant high antiproliferative activity. These compounds were previously assessed as Pgp modulators, at non-cytotoxic doses, on MDR1-mouse lymphoma cells [3]. A regression analysis between the antiproliferative activity presented herein and the previously assessed Pgp modulatory effect showed a strong relation between the compounds that presented both high Pgp modulation and cytotoxicity.

Acknowledgements: FCT, Portugal (PTDC/QUI-QUI/099815/2008; PTDC/QEQ-MED/0905/2012; SFRH/BD/72915/2010).

References:

[1] Hall MD, Handley MD, Gottesman MM. Is resistance useless? Multidrug resistance and collateral sensitivity. Trends Pharmacol Sci 2009; 30: 546 – 556.

[2] Ferreira M-JU, Duarte N, Reis M, Madureira AM, Molnár J. Euphorbia and Momordica metabolites for overcoming multidrug resistance. Phytochem Rev 2014.

[3] Reis M, Ferreira RJ, Santos MMM, dos Santos DJV a, Molnár J, Ferreira M-JU. Enhancing macrocyclic diterpenes as multidrug-resistance reversers: structure-activity studies on jolkinol D derivatives. J Med Chem 2013; 56: 748 – 760.