The Molecular Basis of Synergism between Carboplatin and ABT-737 Therapy Targeting Ovarian Carcinomas

Abstract

Resistance to standard chemotherapy (carboplatin þ paclitaxel) is one of the leading causes of therapeutic failure in ovarian carcinomas. Emergence of chemoresistance has been shown to be mediated in part by members of the Bcl family of proteins including the antiapoptotic protein Bcl-x L , whose expression is correlated with shorter disease-free intervals in recurrent disease. ABT-737 is an example of one of the first small-molecule inhibitors of Bcl-2/Bcl-x L that has been shown to increase the sensitivity of ovarian cancer cells to carboplatin. To exploit the therapeutic potential of these two drugs and predict optimal doses and dose scheduling, it is essential to understand the molecular basis of their synergistic action. Here, we build and calibrate a mathematical model of ABT-737 and carboplatin action on an ovarian cancer cell line (IGROV-1). The model suggests that carboplatin treatment primes cells for ABT-737 therapy because of an increased dependence of cells with DNA damage on Bclx L for survival. Numerical simulations predict the existence of a threshold of Bcl-x L below which these cells are unable to recover. Furthermore, co-plus posttreatment of ABT-737 with carboplatin is predicted to be the best strategy to maximize synergism between these two drugs. A critical challenge in chemotherapy is to strike a balance between maximizing cell-kill while minimizing patient drug load. We show that the model can be used to compute minimal doses required for any desired fraction of cell kill. These results underscore the potential of the modeling work presented here as a valuable quantitative tool to aid in the translation of novel drugs such as ABT-737 from the experimental to clinical setting and highlight the need for close collaboration between modelers and experimental scientists. Cancer Res; 71(3); 705-15. Ó2010 AACR.

Proteasome inhibition leads to altered signaling in the proteome of cisplatin-resistant human ovarian carcinoma cell line

“…These observations are in relation with those determined in CDDP-resistant HL60/B cells with higher levels of NF-κB50 and NF-κB65, where the block of IκB degradation by the proteasome inhibitor PS-I induced cell death [38]. Furthermore, in combination with some conventional chemotherapeutics, proteasome inhibitors including PSI-I, lactacystin and bortezomib increased their cytotoxic activity accompanied by the decrease of several anti-apototic molecules or enhanced apoptotic activity in diverse human cancer cells [39,40]. Further, accumulating evidence suggests that overexpression of antiapoptotic members of the Bcl-2 protein family, Bcl-2, Bcl-xl and MCL-1 confers resistance to several stressors in vitro.…”

Establishment and characterization of a cisplatin-resistant human osteosarcoma cell line

“…Proapoptotic members (Bax, Bak, Bad and Bil) and antiapoptotic members (Bcl-2, Bcl-XL and Mcl-1) of the BCL-2 protein family participate in these lethal cascades, and the majority have been shown to modulate the cellular response to cisplatin. Several studies have found that Bax deficiency and overexpression of BCL-2 conferred resistance to CDDP and to several other stressors in vitro (26,27). In the present study, we compared the expression levels of BCL-2 and Bax in the SOSP-9607 and SOSP-9607/CDDP cells, yet no difference was noted between the resistant cells and the parental cells.…”

Mathematical models of breast and ovarian cancers

“…In a different attempt to model combination therapy, Jain et al developed a mathematical model of ovarian cancer xenograft growth to study the effect of carboplatin, and ABT-737, a small-molecule inhibitor of anti-apoptotic proteins Bcl-2 and Bcl-xL, on tumor growth inhibition 133 . Their model of ovarian cancer growth and treatment was based on a coupled system of ODEs and PDEs 134 , representing the temporal dynamics of proliferating and arrested cancer cells, and concentrations of the two drugs inside the peritoneum, plasma and tissue.…”