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

Rattanaburee, Thidarath; Tanawattanasuntorn, Tanotnon; Thongpanchang, Tienthong; Tipmanee, Varomyalin; Graidist, Potchanapond

doi:10.3390/molecules26154537

Cited by 7 publications

(7 citation statements)

References 59 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%

“…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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“…Furthermore, trans-(−)-kusunokinin binding energies were lower than trans-(+)-kusunokinin binding energies in every protein studied, indicating that the trans-(−)-isomer was a potent form in the racemic compounds [43]. The different actions of extracted trans-(−)kusunokinin and synthetic trans-(±)-kusunokinin were observed and hypothesized to be due to racemic compound nature and purity [41,42].…”

Section: Discussionmentioning

confidence: 93%

“…The previous study hypothesized that the trans-(−)-isoform was the preferred active form in the trans racemic mixture [43], binding CSF1R at the juxtamembrane region (JM) in the same way that pexidartinib does, resulting in suppression of CSF1R and its downstream molecules on breast cancer cells [42]. Other trans-(−)-kusunokinin targets include mmp12, Hsp90a, cyclinB1, MEK1, MEK2 and AKR1B1, whereas the trans-(+)-isoform was predicted to bind HER2, CDK4 and PI3K, but its binding energies did not exceed those of the trans-(−)-isoform in any docked proteins [42][43][44]. Cis-(±)-kusunokinin isomers have been found in Virola sebifera [45] and Acanthopanax chiisanensis [46] and have also been synthesized [47].…”

Section: Introductionmentioning

confidence: 99%

Potential Stereoselective Binding of Trans-(±)-Kusunokinin and Cis-(±)-Kusunokinin Isomers to CSF1R

Ayudhya¹,

Graidist²,

Tipmanee³

2022

Molecules

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Breast cancer cell proliferation and migration are inhibited by naturally extracted trans-(−)-kusunokinin. However, three additional enantiomers of kusunokinin have yet to be investigated: trans-(+)-kusunokinin, cis-(−)-isomer and cis-(+)-isomer. According to the results of molecular docking studies of kusunokinin isomers on 60 breast cancer-related proteins, trans-(−)-kusunokinin was the most preferable and active component of the trans-racemic mixture. Trans-(−)-kusunokinin targeted proteins involved in cell growth and proliferation, whereas the cis-(+)-isomer targeted proteins involved in metastasis. Trans-(−)-kusunokinin targeted CSF1R specifically, whereas trans-(+)-kusunokinin and both cis-isomers may have bound AKR1B1. Interestingly, the compound’s stereoisomeric effect may influence protein selectivity. CSF1R preferred trans-(−)-kusunokinin over trans-(+)-kusunokinin because the binding pocket required a ligand planar arrangement to form a π-π interaction with a selective Trp550. Because of its large binding pocket, EGFR exhibited no stereoselectivity. MD simulation revealed that trans-(−)-kusunokinin, trans-(+)-kusunokinin and pexidartinib bound CSF1R differently. Pexidartinib had the highest binding affinity, followed by trans-(−)-kusunokinin and trans-(+)-kusunokinin, respectively. The trans-(−)-kusunokinin-CSF1R complex was found to be stable, whereas trans-(+)-kusunokinin was not. Trans-(±)-kusunokinin, a potential racemic compound, could be developed as a selective CSF1R inhibitor when combined.

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“…(

)KU was predicted to bind to the juxtamembrane region and form π–π stacking at the binding site of CSF1R [ 12 ]. Moreover, it also binds to the ATP binding domain of HER2 but revealed low binding affinity and a different mode of action from HER2 inhibitor (neratinib) [ 27 ]. Recently, (

)KU was predicted as an inhibitor of AKR1B1, the new target that plays an important role in cellular oxidative stress and the EMT process on cancer cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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Synthetic trans-()-kusunokinin (()KU), a potential anticancer substance, was revealed to have an inhibitory effect on breast cancer. According to the computational modeling prediction, AKR1B1, an oxidative stress and cancer migration protein, could be a target protein of trans-()-kusunokinin. In this study, we determined the binding of ()KU and AKR1B1 on triple-negative breast and non-serous ovarian cancers. We found that ()KU exhibited a cytotoxic effect that was significantly stronger than zopolrestat (ZP) and epalrestat (EP) (known AKR1B1 inhibitors) on breast and ovarian cancer cells. ()KU inhibited aldose reductase activity that was stronger than trans-()-arctiin (()AR) but weaker than ZP and EP. Interestingly, ()KU stabilized AKR1B1 on SKOV3 and Hs578T cells after being heated at 60 and 75 °C, respectively. ()KU decreased malondialdehyde (MDA), an oxidative stress marker, on Hs578T cells in a dose-dependent manner and the suppression was stronger than EP. Furthermore, ()KU downregulated AKR1B1 and its downstream proteins, including PKC-δ, NF-κB, AKT, Nrf2, COX2, Twist2 and N-cadherin and up-regulated E-cadherin. ()KU showed an inhibitory effect on AKR1B1 and its downstream proteins, similar to siRNA–AKR1B1. Interestingly, the combination of siRNA–AKR1B1 with EP or ()KU showed a greater effect on the suppression of AKR1B1, N-cadherin, E-cadherin and NF-κB than single treatments. Taken together, we concluded that ()KU-bound AKR1B1 leads to the attenuation of cellular oxidative stress, as well as the aggressiveness of breast cancer cell migration.

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

Cited by 7 publications

References 59 publications

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

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

Potential Stereoselective Binding of Trans-(±)-Kusunokinin and Cis-(±)-Kusunokinin Isomers to CSF1R

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

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