Effects of trans‑(±)‑kusunokinin on chemosensitive and chemoresistant ovarian cancer cells

Abstract

Ovarian cancer ranks eighth in cancer incidence and mortality among women worldwide. Cisplatin-based chemotherapy is commonly used for patients with ovarian cancer. However, the clinical efficacy of cisplatin is limited due to the occurrence of adverse side effects and development of cancer chemoresistance during treatment. Trans-(±)-kusunokinin has been previously reported to inhibit cell proliferation and induce cell apoptosis in various cancer cell types, including breast, colon and cholangiocarcinoma. However, the potential effects of (±)-kusunokinin on ovarian cancer remains unknown. In the present study, chemosensitive ovarian cancer cell line A2780 and chemoresistant ovarian cancer cell lines A2780cis, SKOV-3 and OVCAR-3 were treated with trans-(±)-kusunokinin to investigate its potential effects. MTT, colony formation, apoptosis and multi-caspase assays were used to determine cytotoxicity, the ability of single cells to form colonies, induction of apoptosis and multi-caspase activity, respectively. Moreover, western blot analysis was performed to determine the proteins level of topoisomerase II, cyclin D1, CDK1, Bax and p53-upregulated modulator of apoptosis (PUMA). The results demonstrated that trans-(±)-kusunokinin exhibited the strongest cytotoxicity against A2780cis cells with an IC 50 value of 3.4 µM whilst also reducing the colony formation of A2780 and A2780cis cells. Trans-(±)-kusunokinin also induced the cells to undergo apoptosis and increased multi-caspase activity in A2780 and A2780cis cells. This compound significantly downregulated topoisomerase II, cyclin D1 and CDK1 expression, but upregulated Bax and PUMA expression in both A2780 and A2780cis cells. In conclusion, trans-(±)-kusunokinin suppressed ovarian cancer cells through the inhibition of colony formation, cell proliferation and the induction of apoptosis. This pure compound could be a potential targeted therapy for ovarian cancer treatment in the future. However, studies in an animal model and clinical trial need to be performed to support the efficacy and safety of this new treatment.

Trans-(±)-Kusunokinin Binding to AKR1B1 Inhibits Oxidative Stress and Proteins Involved in Migration in Aggressive Breast Cancer

“…In this study, ( )KU had IC 50 values on ovarian cancer (A2780, SKOV3 and OVCAR3) that were similar to CIS (chemotherapeutic drug for ovarian cancer treatment) and our previous report [ 10 ]. ( )KU showed strong cytotoxicity against breast cancer cell lines on both minimally potential migration (MCF7) and aggressive migration (BT549 and Hs578T).…”

“…Previously, we reported that kusunokinin had a cytotoxic effect on cancer cell lines, for instance, ovarian cancer (A2780, A2780cis, SKOV3 and OVCAR3), colon cancer (HT-29), cholangiocarcinoma (KKU-M213 and KKU-K100) and several breast cancer subtypes, including luminal A (MCF7), basal-A (MDA-MB-468) and basal-B (MDA-MB-231) [ 9 , 10 ]. The natural ( )KU showed significantly increased apoptosis on MCF7 and MDA-MB-468 cells after treatment for 24 h. ( )KU decreased anti-apoptotic protein (bcl2) and increased apoptotic protein (bax, cytochrome c, caspase-7 cleaved and caspase-8 cleaved) on MCF-7 cells at 72 h [ 25 ].…”

“…This synthetic compound significantly enhanced multi-caspase activity (caspase-1, -3, -4, -5, -6, -7, -8 and -9) on MCF7 cells in a time- and dose-dependent manner [ 9 ]. In addition, ( )KU significantly increased the number of early/late/total apoptotic cells, multi-caspase activity and apoptotic proteins (bax and PUMA) in ovarian cancer cells (A2780 and A2780cis) at 72 h [ 10 ]. All these previous studies confirm that ( )KU had a cytotoxic effect through the induction of apoptosis.…”

“…The synthetic racemic trans -( )-kusunokinin (( )KU) showed the inhibition of proliferation through significantly decreased topoisomerase II and cyclin D1 and increased p21 on breast, colon, cholangiocarcinoma and ovarian cancer cell lines [ 9 , 10 ]. In addition, trans -( )-kusunokinin (( )KU) inhibits tumor growth and migration with no side effects in NMU-induced mammary tumor rats [ 11 ].…”

Anticancer Activity of (±)-Kusunokinin Derivatives towards Cholangiocarcinoma Cells

“…In our previous study, we reported that natural (−)-kusunokinin showed anticancer activity against breast, colon and lung cancer [ 19 , 21 ]. In addition, the synthetic (±)-kusunokinin racemic-compounds also exhibited cytotoxic activity in many cancer cells including breast, cholangiocarcinoma, colon, and ovarian cancer cells [ 20 , 24 ]. In this present study, we aimed to evaluate the cytotoxicity of (±)-kusunokinin derivatives ((±)-TTPG-A and (±)-TTPG-B) in aggressive cancer-cells.…”