Introduction/Background HGSOC is the deadliest gynecologic cancer. Most of cases end up recurring and dying from metastatic/resistant disease. Cancer-initiating cells (CIC) constitute the subpopulation responsible for the acquisition of drug resistance and the progression/recurrence of the disease. ALDH1A1 activity is commonly increased in CICs and correlates with drug resistance (by drug detoxification), metastasis and prognosis. Our group has demonstrated that simvastatin, a lipophilic form of statins, chemo-sensitizes ovarian cancer cells and interferes with cell plasticity of HGSOC-derived CICs reducing metastasis in a mevalonate-dependent manner. Here, we study whether the combination of simvastatin with metronomic cyclophosphamide could be effective in treating recurrent/resistant HGSOC.
Methodology CICs were isolated from HeyA8 ovarian cancer cell line and from ascites collected from chemo-näive and chemoresistant recurrent advanced HGSOCs using stem cell-selecting culture conditions. CICs were treated with simvastatin (1, 2 and 5 µM), mafosfamide (4,7 µM) or its combination (24-hour pulse, 4 days). The induction of apoptosis was measured by detection of PARP cleavage by immunoblotting. ALDH1A1 enzyme levels were determined by q-PCR and immunoblotting. Xenograft tumors were generated by injecting CICs intraperitoneally (IP) in NSG mice. Once established xenografts, mice were treated with placebo, simvastatin (2 mg/kg/day IP), cyclophosphamide (20 mg/kg/day PO) or its combination (n=6 per group). Ascites volume, body weight, distribution of metastatic foci, and ALDH1A immunostaining at the injection site were measured. Survival curves were also made.
Results Repeated doses of this combination significantly reduced ALDH1A1 expression and induced PARP cleavage compared with each reagent alone in vitro. More importantly, simvastatin reduced ALDH1A1 expression, and the combination diminished ascites volume, metastatic disease, and prolonged survival in vivo.
Conclusion Our findings support the effectiveness of simvastatin plus metronomic cyclophosphamide in pre-clinical models of recurrent/resistant HGSOCs.The explanatory mechanism involves a decrease in ALDH1A1 activity (an enzyme regulating the cyclophosphamide detoxification) induced by simvastatin (research support by Fondecyt 1160800)
Disclosure Nothing to disclose.
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