ABT‑737 and pictilisib synergistically enhance pitavastatin‑induced apoptosis in ovarian cancer cells

Abstract

Abstract. There is considerable interest in redeploying drugs for use in combination with other oncology therapeutics. The single-agent activity of statins in ovarian cancer has been widely reported, however the drug concentration required to cause cell death is considerably higher than that achieved in patients receiving statin treatment for hypercholesterolemia. Unfortunately, statins can cause myopathy when administered in high doses. One solution to this is to identify drugs that could be used in combination with statins to reduce the dose required and those that may potentially reduce the incidence of adverse side effects. When the BH3 mimetic ABT-737, or the phosphatidylinositol 3-kinase inhibitor pictilisib, were combined with pitavastatin in cell growth assays using Ovcar-3 and Igrov-1 cells, the drug combinations were more effective than pitavastatin alone. In support of this, ABT-737 or pictilisib markedly increased cell death induced by pitavastatin in several ovarian cancer cell lines. The drugs were also synergistic in apoptosis assays. These observations suggested that either BH3 mimetics or pictilisib in combination with pitavastatin could be used in a subset of ovarian tumours, particularly those sensitive to BH3 mimetics, and phosphatase and tensin homolog inhibition, in the treatment of ovarian cancer.

Mechanisms of Taxane Resistance

“…Multiple studies have utilized specific inhibitors of the pathway (AZD8835, AZD8186, and D-11688) and silencing RNA to increase the number of apoptotic cells in a dose-dependent manner, reduce anchorage-independent growth, and sensitize resistant cells to chemotherapy [ 251 , 252 , 253 ]. Interestingly, the combination of a PI3K pathway inhibitor with a BCL-2 family inhibitor showed synergistic effects in increasing cell death [ 254 , 255 ]. It could be that because of the many facets in the PI3K/AKT/mTOR pathway and the fact that the pathway itself has a major role in so many different cellular activities, inhibitors of PI3K/AKT/mTOR should be used in addition to inhibitors of other anti-apoptotic pathways in order to successfully enforce apoptosis in taxane-resistant cells.…”

Targeting the Mevalonate Pathway in Cancer

“…Recent studies found that statins sensitize cancer cells to intrinsic apoptosis by the novel class of apoptosis-inducing drugs BH3 mimetics [124,125]. Such agents induce rapid apoptosis when a cell is mitochondrially primed for death [126].…”

Therapeutic Inducers of Apoptosis in Ovarian Cancer

“…Navitoclax also increased carboplatin sensitivity in one of three primary cultures derived from ascites. Later, other studies suggested that phosphatidylinositol 3-kinase (PI3K) pathway inhibitor (pictilisib) and navitoclax combination treatment resulted in enhanced pitavastatin-induced apoptosis in ovarian cancer cells [33]. This evidence suggests that Navitoclax is able to enhance the efficacy of chemotherapy drugs in ovarian cancer cells.…”