Epidemiological studies indicate that cancer patients who also use HMGCoA reductase inhibitors (statins) for cholesterol control have better cancer outcomes. More than 160 proteins require, for activity, prenylation by down-stream products of HMGCoA reductase. Although six of these are proto-oncoproteins, a clear mechanism of action has not been identified. Prenylated proteins are important in many normal cellular processes that impact cancer outcomes, including proliferation, apoptosis, drug sensitivity, migration, inflammation and immunity.
Using platinum resistant high grade serous ovarian cancer (HGSC) cell lines cultured in vitro, we demonstrated that cell proliferation was inhibited only at clinically non-feasible doses of the lipophilic statins, simvastatin and atorvastatin (>0.2 mM). This was largely reversible by addition of the isoprenoid geranylgeranyl pyrophosphate rather than farnesyl pyrophosphate. However, in IGROV-1 cells, combinatorial treatment with cisplatin and 0.2 mM atorvastatin induced significantly more apoptosis than either drug alone. This regimen also induced S-phase cell cycle arrest. Moreover, sequential treatments with these agents abrogated these effects.
As tumour associated macrophages (TAM) can mediate chemoresistance, we investigated the apoptotic effects of statins on HGSC cells co-cultured with macrophages isolated from HGSC patient ascites. Compared to non-co-cultured cells, this revealed significantly increased apoptosis for combinations of cisplatin with either atorvastatin or simvastatin. Additionally, in IGROV-1 cells, shRNA knockdown of IL-6, (a pleiotropic cytokine which mediates platinum resistance) enhanced apoptosis compared to scrambled controls, with and without macrophage co-culture. Phenotypic characterisation of these macrophages is ongoing.
Overall, the beneficial effects witnessed varied amongst different HGSC cell lines, and also between different statins. As statins impact many normal and tumour associated cellular processes, their use in ovarian cancer therapeutics will require the development of suitable biomarkers that will assist appropriate stratification of ovarian cancer patients with platinum resistance, who could gain durable responses with platinum rechallenge in combination with statin therapy.