Inhibition of CSF1R and AKT by (±)-kusunokinin hinders breast cancer cell proliferation

Rattanaburee, Thidarath; Tipmanee, Varomyalin; Tedasen, Aman; Thongpanchang, Tienthong; Graidist, Potchanapond

doi:10.1016/j.biopha.2020.110361

Cited by 21 publications

(43 citation statements)

References 39 publications

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“…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 ). Synthetic racemic trans-(±)-kusunokinin, which consists of trans-(−)-kusunokinin and trans-(+)-kusunokinin ( Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Synthetic racemic trans-(±)-kusunokinin, which consists of trans-(−)-kusunokinin and trans-(+)-kusunokinin ( Fig. 1A ), can reduce CSF1R protein expression and subsequently inhibit AKT and STAT3 activity and the expression of downstream molecules cyclin D1 and CDK1, leading to cell cycle arrest at the G 2 /M phase in MCF-7 cells ( 30 , 31 ). Additionally, this effective compound has been demonstrated to decrease Ras, ERK and cyclin B1 expression in breast cancer cells ( 32 ).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…The Luciferase duplex (Photinus pyralis (American firefly) luciferase gene) (Cat No: P-002099-01-20, Dharmacon, Lafayette, CO, USA) was used as the siRNA control experiment. siRNAs were transfected using Lipofectamine ® RNAiMAX (Invitrogen, Waltham, MA, USA), according to the manufacturer's instructions, as previously described [21]. Briefly, MCF-7 cells were seeded in 24 well plates for 24 h and transfected with 100 nM siRNA-HER2 or 100 nM siRNA-Luciferase.…”

Section: In Vitro Transfection Of Small Interfering Rnamentioning

confidence: 99%

“…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]. Interestingly, the synthetic (±)-kusunokinin inhibits the proliferation of breast cancer cells through the binding and the suppression of CSF1R, which consequently decreases AKT and the downstream proteins in cell proliferation (CyclinD1 and CDK) [21]. Using computational analysis, trans-(−)-kusunokinin binds AKR1B1, and the upstream molecules of the AKT signaling protein in migration [22].…”

Section: Introductionmentioning

confidence: 99%

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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“…Recently, Rattanaburee and colleagues [127] investigated the potential target responsible for the antiproliferative activity of synthetic (±)-kusunokinin. They concluded that the cytostatic effects of this molecule in breast cancer cells relied on its ability to suppress the colony stimulating factor-1 receptor (CSF1R), whose downregulation then affected Akt and its downstream molecules cyclin D1 and CDK1 [127]. Of note, the affinity of the synthetic (±)-kusunokinin for CSF1R is higher than that of natural (−)-kusunokinin, underlying the importance to use these molecules to improve their affinity for the target.…”

Section: Other Compounds From Piper Nigrum With Anticancer Potentialmentioning

confidence: 99%

Overview of the Anticancer Potential of the “King of Spices” Piper nigrum and Its Main Constituent Piperine

Turrini

Sestili

Fimognari

2020

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The main limits of current anticancer therapy are relapses, chemoresistance, and toxic effects resulting from its poor selectivity towards cancer cells that severely impair a patient’s quality of life. Therefore, the discovery of new anticancer drugs remains an urgent challenge. Natural products represent an excellent opportunity due to their ability to target heterogenous populations of cancer cells and regulate several key pathways involved in cancer development, and their favorable toxicological profile. Piper nigrum is one of the most popular spices in the world, with growing fame as a source of bioactive molecules with pharmacological properties. The present review aims to provide a comprehensive overview of the anticancer potential of Piper nigrum and its major active constituents—not limited to the well-known piperine—whose undeniable anticancer properties have been reported for different cancer cell lines and animal models. Moreover, the chemosensitizing effects of Piper nigrum in association with traditional anticancer drugs are depicted and its toxicological profile is outlined. Despite the promising results, human studies are missing, which are crucial for supporting the efficacy and safety of Piper nigrum and its single components in cancer patients.

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Inhibition of CSF1R and AKT by (±)-kusunokinin hinders breast cancer cell proliferation

Cited by 21 publications

References 39 publications

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

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

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

Overview of the Anticancer Potential of the “King of Spices” Piper nigrum and Its Main Constituent Piperine

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