These results are significant when considering that clinically, all recurrent ovarian cancers will eventu ally be platinum resistant. Cabozantinib cancer Interestingly, BT IC50 values observed for various ovarian cancer cell lines are signifi cantly below the clinically tolerable doses of BT for humans. In several published studies, chronic BT dosing up to 50 mg kg every other day was well tolerated with the 40 mg kg dose level best tolerated. Fifty mg kg in three divided alternate daily doses for 5 days will main tain serum levels of BT in the range of 140 to 550 uM in rabbits, dogs and humans. Based on the fact that BT exerts similar cytotoxic effects on cisplatin sensitive and resistant ovarian cancer cell lines with clinically tolerable IC50 values, it is reasonable to speculate that BT may be useful in halting ovarian cancer cell growth irrespective of the sensitivity that cells may display to cisplatin, and this merits further exploration.

It is well known that invalid apoptosis pathway has often been one of the hallmarks of cancer cells and an important cause of resistance to cytotoxic agents. It is therefore es sential to focus on type of cell death induced by therapeutic agents. Ability to induce apoptosis is a critical factor for ef fective treatment against cancer. Previous reports show the inhibitory effect of BT on cervical cancer cell growth via induction of caspase 3 7 activity. Our results also indi cate that ovarian cancer cells undergo apoptosis upon BT treatment initially at lower concentrations.

Hallmarks of apoptosis, such as nuclear condensation, DNA fragmenta tion, and loss of mitochondrial potential, were observed fur ther demonstrating that BT triggers apoptosis in ovarian cancer cells. However, at higher concentrations, no caspase activity was detected while LDH was detected, indicating that cells die via necrosis at higher concentrations. The abil ity of BT to induce cell death via apoptosis makes this drug a good candidate for the treatment of ovarian cancer. This study type 2 diabetes also demonstrates that BT induces apop tosis in ovarian cancer cells via activation of proteolytic effector caspases such as Caspase 3 and 7 and subse quent cleavage inactivation of PARP 1. Apoptosis is known to be mediated by two path ways, the extrinsic and the intrinsic. The majority of anticancer drugs induce apoptosis via the intrinsic. Mito chondria are considered to be both a source and a target of ROS. Although we did not focus on which apoptotic pathway was induced by BT, decreased mitochondrial transmembrane potential following BT treatment impli cates the intrinsic pathway. Disruption of mitochondrial potential can lead to oxidation of mito chondrial pores by ROS, resulting in release of cyto chrome C into the cytosol.