(−)-Kusunokinin inhibits breast cancer in N-nitrosomethylurea-induced mammary tumor rats

Tedasen, Aman; Dokduang, Sirinapa; Sukpondma, Yaowapa; Lailerd, Narissara; Madla, Siribhorn; Sriwiriyajan, Somchai; Rattanaburee, Thidarath; Tipmanee, Varomyalin; Graidist, Potchanapond

doi:10.1016/j.ejphar.2020.173311

Cited by 16 publications

(30 citation statements)

References 37 publications

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“…In female Sprague-Dawly rats, mammary tumors were induced through an intraperitoneal injection of 50 mg/kg NMU. (−)-Kusunokinin (7 or 14 mg/kg injected subcutaneously) significantly suppressed tumor growth and no toxic effects were recorded in any of the analyzed organs (heart, liver, lung, spleen, and kidney) or in hematologic and clinical chemistry parameters [128], suggesting a safe profile of this lignan. Furthermore, the study analyzed the anticancer mechanisms of the molecule in breast tumor tissue of treated rats [126].…”

Section: Other Compounds From Piper Nigrum With Anticancer Potentialmentioning

confidence: 88%

“…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. A very recent study investigated, for the first time, the anticancer effects of (−)-kusunokinin in vivo [128]. In female Sprague-Dawly rats, mammary tumors were induced through an intraperitoneal injection of 50 mg/kg NMU.…”

Section: Other Compounds From Piper Nigrum With Anticancer Potentialmentioning

confidence: 99%

“…Furthermore, the study analyzed the anticancer mechanisms of the molecule in breast tumor tissue of treated rats [126]. (−)-Kusunokinin (14 mg/kg) reduced the levels of signaling proteins, i.e., the proto-oncogene tyrosine-protein kinase Src (c-Src), phosphatidylinositol 3-kinases (PI3K), Akt, and p-ERK1/2 and their downstream targets, such as proteins involved in cell-cycle regulation (c-myc, E2F1, CDK1, and cyclin B1) and cell migration (E-cadherin, MMP-2, and MMP-9) [128].…”

Section: Other Compounds From Piper Nigrum With Anticancer Potentialmentioning

confidence: 99%

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

Turrini

Sestili

Fimognari

2020

Toxins

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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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Section: Other Compounds From Piper Nigrum With Anticancer Potentialmentioning

confidence: 88%

Section: Other Compounds From Piper Nigrum With Anticancer Potentialmentioning

confidence: 99%

Section: Other Compounds From Piper Nigrum With Anticancer Potentialmentioning

confidence: 99%

See 1 more Smart Citation

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

Turrini

Sestili

Fimognari

2020

Toxins

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“…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%

“…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]. 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].…”

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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The anti-cancer potential of 2,4,6 tris-methyphenylamino1,3,5-triazine compound against mammary glands cancer: Via down-regulating the hormonal, inflammatory mediators, and oxidative stress

et al. 2021

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(−)-Kusunokinin inhibits breast cancer in N-nitrosomethylurea-induced mammary tumor rats

Cited by 16 publications

References 37 publications

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

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

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

The anti-cancer potential of 2,4,6 tris-methyphenylamino1,3,5-triazine compound against mammary glands cancer: Via down-regulating the hormonal, inflammatory mediators, and oxidative stress

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