Ratio-Dependent Synergism of a Doxorubicin and Olaparib Combination in 2D and Spheroid Models of Ovarian Cancer

Ovarian cancer is the fourth leading cause of death in women in developed countries. Even though patients with the most lethal form of the disease (HGSOC; high grade serous ovarian cancer) respond well to initial treatment, they often relapse with progressively resistant disease. Inhibitors of the poly(ADP-ribose) polymerase (PARP) enzymes are a relatively new class of molecularly targeted small molecule drugs that show promise in overcoming resistance. The present study explores the combination of a DNA damaging agent, doxorubicin (DOX), with the PARP inhibitor, olaparib (OLP), in order to achieve optimal synergy of both drugs in serous ovarian cancer. This drug combination was evaluated and optimized in 2D monolayers and 3D multicellular tumor spheroids (MCTS) using a genetically and histologically characterized panel of nine OC cell lines with or without BRCA1 or BRCA2 mutations. Combination index (CI) values of DOX and OLP were determined using the Chou and Talalay method. The potency of this drug combination was found to rely heavily on the molar ratios at which the two drugs are combined. In general, MCTS growth inhibition was reflective of the patterns predicted by the CI values obtained in monolayers. Promising combination ratios identified in this study warrant further preclinical and clinical investigation.