Anticancer activity of synthetic (±)-kusunokinin and its derivative (±)-bursehernin on human cancer cell lines

Rattanaburee, Thidarath; Thongpanchang, Tienthong; Wongma, Krittaphat; Tedasen, Aman; Sukpondma, Yaowapa; Graidist, Potchanapond

doi:10.1016/j.biopha.2019.109115

Cited by 19 publications

(30 citation statements)

References 48 publications

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“…The π-π stacking with Phe159 was also found in the synthetic inhibitor 03q. The synonymous binding manner of trans-(−)-kusunokinin was also previously documented in the CSF1R [19,20] and AKR1B1 [22]. In short, trans-(−)-kusunokinin and trans-(+)-kusunokinin could bind HER2 in some ATP binding regions using π-π stacking and hydrophobic interactions.…”

Section: Discussionsupporting

confidence: 58%

“…The molecular docking approach has many limitations in its representation of atomistic information for drug-protein behaviors, such as lack of temperature and dynamics behaviors, hydrogen bonding within a protein-drug complex due to the water and ionic strength of the environment [19,20,36]. MD simulation with full surroundings would provide more realistic factors, and thus the justification of binding behaviors of the compounds towards HER2 could be more consolidated.…”

Section: Discussionmentioning

confidence: 99%

“…Trans-(±)-kusunokinin was synthesized following the procedure reported in our previous publication [19]. Neratinib (HKI-272) was obtained from Selleck Chemicals (CAS No: S2150, Houston, TX, USA).…”

Section: Compound Acquisitionmentioning

confidence: 99%

“…This synthetic compound exhibits similar cytotoxic activity on breast and colon cancer, the same as the extract. The synthetic trans-(±)-kusunokinin is found to suppress topoisomerase II, STAT3, CyclinD1 and p21 on breast cancer and cholangiocarcinoma cells [19]. For the in vivo study, trans-(−)-kusunokinin decreases tumor growth and migration without side effects on blood parameters and the clinical chemistry of renal and liver function [20].…”

Section: Introductionmentioning

confidence: 99%

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Trans-(−)-Kusunokinin: A Potential Anticancer Lignan Compound against HER2 in Breast Cancer Cell Lines?

et al. 2021

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Trans-(−)-kusunokinin, an anticancer compound, binds CSF1R with low affinity in breast cancer cells. Therefore, finding an additional possible target of trans-(−)-kusunokinin remains of importance for further development. Here, a computational study was completed followed by indirect proof of specific target proteins using small interfering RNA (siRNA). Ten proteins in breast cancer were selected for molecular docking and molecular dynamics simulation. A preferred active form in racemic trans-(±)-kusunokinin was trans-(−)-kusunokinin, which had stronger binding energy on HER2 trans-(+)-kusunokinin; however, it was weaker than the designed HER inhibitors (03Q and neratinib). Predictively, trans-(−)-kusunokinin bound HER2 similarly to a reversible HER2 inhibitor. We then verified the action of (±)-kusunokinin compared with neratinibon breast cancer cells (MCF-7). (±)-Kusunokinin exhibited less cytotoxicity on normal L-929 and MCF-7 than neratinib. (±)-Kusunokinin and neratinib had stronger inhibited cell proliferation than siRNA-HER2. Moreover, (±)-kusunokinin decreased Ras, ERK, CyclinB1, CyclinD and CDK1. Meanwhile, neratinib downregulated HER, MEK1, ERK, c-Myc, CyclinB1, CyclinD and CDK1. Knocking down HER2 downregulated only HER2. siRNA-HER2 combination with (±)-kusunokinin suppressed HER2, c-Myc, CyclinB1, CyclinD and CDK1. On the other hand, siRNA-HER2 combination with neratinib increased HER2, MEK1, ERK, c-Myc, CyclinB1, CyclinD and CDK1 to normal levels. We conclude that trans-(±)-kusunokinin may bind HER2 with low affinity and had a different action from neratinib.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Compound Acquisitionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Trans-(−)-Kusunokinin: A Potential Anticancer Lignan Compound against HER2 in Breast Cancer Cell Lines?

et al. 2021

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“…Trans-(−)-kusunokinin has also been found to decrease the expression of migratory proteins MMP-2, MMP-9 and E-cadherin ( 29 ). Furthermore, synthetic trans-(±)-kusunokinin was demonstrated to induce cytotoxicity against breast cancer and cholangiocarcinoma cells whilst increasing multi-caspase activity ( 30 ). Trans-(−)-kusunokinin can also interact with colony stimulating factor 1 receptor (CSF1R) and HER, proteins associated with cancer cell proliferation ( 31 , 32 ) and aldo-keto reductase family 1 member B, a protein associated with migration (AKR1B1) ( 33 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Modern Photocatalytic Strategies in Natural Product Synthesis

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Vega‐Peñaloza

et al. 2023

Modern Photocatalytic Strategies in Natural Product Synthesis

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Anticancer activity of synthetic (±)-kusunokinin and its derivative (±)-bursehernin on human cancer cell lines

Cited by 19 publications

References 48 publications

Trans-(−)-Kusunokinin: A Potential Anticancer Lignan Compound against HER2 in Breast Cancer Cell Lines?

Trans-(−)-Kusunokinin: A Potential Anticancer Lignan Compound against HER2 in Breast Cancer Cell Lines?

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

Modern Photocatalytic Strategies in Natural Product Synthesis

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