Z Gastroenterol 2014; 52 - P_4_12
DOI: 10.1055/s-0033-1360965

Doxorubicin induces tumorigenicity and chemotherapy resistance of residual hepatocellular carcinoma cells in vitro

S Buschauer 1, C Hellerbrand 1
  • 1University Hospital Regensburg, Department of Internal Medicine I, Regensburg, Germany

Transarterial chemoembolization (TACE) is a well-established therapeutic option in the treatment of hepatocellular carcinoma (HCC) with doxorubicin (DOX) as most widely used chemotherapeutic drug. Although patients undergoing TACE may have prolonged survival, local recurrence occurs in a significant number of cases. However, the tumorigenicity of residual HCC cells is not known and there exists no information regarding DOX-tolerance in case of second TACE-treatment.

The aim of this study was to establish an in vitro model to study HCC cells, which escape doxorubicin therapy.

Methods and Results: Initially, we determined the toxic dose range of DOX for 3 different HCC-cell lines (HepG2, Hep3B and PLC) in vitro. Subsequently, HCC cells were incubated with IC50 for 48h. Subsequently, surviving HCC cells (HCC-surv) were further cultured for 3 weeks and compared to HCC control cells (HCC-ctr) without DOX-exposure. Proliferation did not differ significantly between HCC-surv and HCC-ctr cells. However, migration activity as well as expression of epithelial-mesenchymal transition (EMT) markers SNAIL and SLUG was increased in HCC-surv compared to HCC-ctr. Further, expression of the pro-angiogenetic factor IL-8 was significantly enhanced in HCC-surv cells, and also tolerance for DOX was significantly increased compared to HCC-ctr cells. As most likely explanation for the enhanced DOX-tolerance we observed increased expression of multidrug resistance protein 1 (ABCB1) and multidrug resistance-associated protein 1 (ABCC1) in HCC-surv cells compared to HCC-ctr cells.

Conclusion: Our results show that doxorubicin therapy might induce tumorigenicity of residual HCC cells and might participate to chemoresistance acquisition by selecting tumor cell subpopulations expressing ABCB1 and ABCC1. These findings are of particular importance in understanding the relapses observed after TACE as well as choice of chemotherapeutics in case of second TACE-treatment.