Topotecan synergizes with CHEK1 (CHK1) inhibitor to induce apoptosis in ovarian cancer cells

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.

MicroRNA-106a regulates phosphatase and tensin homologue expression and promotes the proliferation and invasion of ovarian cancer cells

“…The current standard of care includes surgical cytoreduction and platinum-based chemotherapy. Although cytoreductive surgery with chemotherapy can significantly prolong patient survival, most cancers eventually relapse and metastasize, becoming resistant and refractory to standard chemotherapy; the 5-year survival rate is ~30% (3).…”

The role of topotecan in cancer ginecology treatment

“…Предпосылками к изучению топотекана в еженедельном режиме по-служили данные о том, что уровни внутриклеточной топоизомеразы I после воздействия топотекана воз-вращались к исходным показателям через 7 дней [21]. Еще одним интересным свойством препарата являл-ся его синергизм с таргетными агентами: ингибито-рами ангиогенеза, тирозинкиназ и СНЕК1 [22,23]. K. F. McGonigle и H. G. Muntz изучали эффективность и безопасность еженедельного применения топоте-кана 4 мг / м 2 в комбинации с еженедельным приемом бевацизумаба 7 мг / кг.…”

“…Последние данные об иммуномодулирую-щей роли топотекана, показавшие топотеканинду-цированную активность дендритных клеток, CD8 + -и Т-клеток на примере линии рака молочной желе-зы, могут объяснить хороший синергизм действия с антиангиогенным препаратом бевацизумаб [22]. Такая схема может стать альтернативой при лечении опухолей, малочувствительных к стандартной схеме терапии, например серозного рака яичников низ-кой степени злокачественности, а также у больных с резистентными, платинорефрактерными и потен-циально платиночувствительными рецидивами рака яичников, рака тела и шейки матки, рака молочной железы.…”

Conserved molecular mechanisms underlying the effects of small molecule xenobiotic chemotherapeutics on cells

“…The TRAIL receptor antagonists (182)(183)(184)(185)(186) The TRAIL receptor antagonists, hydroxycamptothecin and topotecan, still permit the concomitant binding of the endogenous TRAIL, but decreases the potency of the pressuromodulation effect by causing for a decrease in the affinity of TRAIL R2 for endogenous TRAIL, which is an extremely portent prolonged duration 2ary indirect pressuromodulator multi-subunit poly-meric β-helix-based receptors (187)(188)(189)(190)(191). As such, hydroxycamptothecin and topotecan-mediated CM receptor pressuromodulation antagonism of TRAIL results in TRAIL pressuromodulation-mediated TRAIL R2 chromatin transcription and in auto-induction of TRAIL R2 at the CM (192) as well as in that of the lower-to-higher MW proteins (i.e., VEGF, 20 kDa; p21; p53; topoisomerase I, 90 kDa; HIF1-α, 93 kDa; P-gp, 140 kDa; topoisomerase II-α, 174 kDa) (186,193), but not of the highest MW nuclear division-associated proteins (Ki67, 359 kDa; separase, 230 kDa), in which case, the increased transcription of intermediate MW protein, p53 (53 kDa) (184,186), results in the depletion of free BCL (p53-BCL) and in mitochondrial-mediated oxidative stress sufficient to induce apoptosis (182,183) that maybe associated with a secondary decrease in mitogenesis and cell division (182) in synergism with additional CM receptor pressuromodulation antagonism (185) (Table XI and Fig.…”

“…As such, hydroxycamptothecin and topotecan-mediated CM receptor pressuromodulation antagonism of TRAIL results in TRAIL pressuromodulation-mediated TRAIL R2 chromatin transcription and in auto-induction of TRAIL R2 at the CM (192) as well as in that of the lower-to-higher MW proteins (i.e., VEGF, 20 kDa; p21; p53; topoisomerase I, 90 kDa; HIF1-α, 93 kDa; P-gp, 140 kDa; topoisomerase II-α, 174 kDa) (186,193), but not of the highest MW nuclear division-associated proteins (Ki67, 359 kDa; separase, 230 kDa), in which case, the increased transcription of intermediate MW protein, p53 (53 kDa) (184,186), results in the depletion of free BCL (p53-BCL) and in mitochondrial-mediated oxidative stress sufficient to induce apoptosis (182,183) that maybe associated with a secondary decrease in mitogenesis and cell division (182) in synergism with additional CM receptor pressuromodulation antagonism (185) (Table XI and Fig. 11).…”