Abstract
BackgroundTopotecan (TPT) is a therapeutic option for women with platinum-resistant or -refractory ovarian cancer. However, the dose-limiting toxicity of TPT is myelosuppression. This led us to seek a combination treatment to augment TPT anti-cancer activity in a cancer-targeted manner. Ovarian serous cancers, a major subtype, show dysregulated DNA repair pathway and often display a high level of CHEK1 (CHK1), a cell cycle regulator and DNA damage sensor. CHEK1 inhibitors are a novel approach to treatment, and have been used as single agents or in combination chemotherapy in many cancers.MethodsWe evaluated the cellular effects of TPT in a panel of high grade serous (HGS) and non-HGS ovarian cancer cells. We then determined IC50s of TPT in the absence and presence of CHEK1 inhibitor, PF477736. Synergism between TPT and PF477736 was calculated based on cellular viability assays. Cytotoxic effect of the combined treatment was compared with apoptotic activities by Caspase3/7 activity assay and Western blotting of cleaved-PARP1 and γH2AX.ResultsNon-HGS ovarian cancer cells were generally more sensitive to TPT treatment compared to HGS ovarian cancer cells. When combined with CHEK1 inhibitor, TPT potently and synergistically inhibited the proliferation of HGS ovarian cancer cells. This dramatic synergism in cellular toxicity was consistent with increases in markers of apoptosis.ConclusionsOur findings suggest that the addition of CHEK1 inhibitor increases the response of ovarian cancer cells to TPT. Furthermore, reduced dosages of both drugs achieved maximal cytotoxic effects by combining TPT with CHEK1 inhibitor. This strategy would potentially minimize side effects of the drugs for extended clinical benefit.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1231-z) contains supplementary material, which is available to authorized users.
Highlights
Topotecan (TPT) is a therapeutic option for women with platinum-resistant or -refractory ovarian cancer
In HSG ovarian cancers, p53 is either null or mutated, increasing the cellular dependency on CHEK1/2 for DNA damage repair and survival. Supporting this notion, we recently showed that CHEK1 gene is overexpressed in most cases of high-grade serous (HGS) ovarian cancer as compared to normal ovarian surface epithelium in The Cancer Genome Atlas (TCGA) dataset, suggesting that CHEK1 is required for cells to tolerate the defective DNA repair intrinsic to HGS cancers [2,6]
We initially determined cytotoxicity of TPT in a panel of 4 non-HGS, and 6 HGS ovarian cancer cell lines including PEO1 and PEO4, a pair of HGS ovarian cancer cell lines established from the same patient before and after platinum-based chemotherapy [13]
Summary
Topotecan (TPT) is a therapeutic option for women with platinum-resistant or -refractory ovarian cancer. A major subtype, show dysregulated DNA repair pathway and often display a high level of CHEK1 (CHK1), a cell cycle regulator and DNA damage sensor. CHEK1 inhibitors are a novel approach to treatment, and have been used as single agents or in combination chemotherapy in many cancers. Ovarian cancer has a high response rate, but most cancers eventually relapse and metastasize, becoming resistant and refractory to standard chemotherapy. Treatment approaches commonly include chemotherapies that induce DNA damage, since the ovarian cancer cell will die when it is incapable of recovering from injury to its DNA. The topoisomerase I inhibitor topotecan (TPT) is active against many cancer types including platinumsensitive and resistant ovarian cancers [4,5]. Side effects of TPT and other DNA-damaging agents include low blood counts, nausea, vomiting, diarrhea, and
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