2. Academic Validation
  3. (-)-Kusunokinin inhibits breast cancer in N-nitrosomethylurea-induced mammary tumor rats

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

  • Eur J Pharmacol. 2020 Sep 5;882:173311. doi: 10.1016/j.ejphar.2020.173311.
Aman Tedasen 1,  Sirinapa Dokduang 2,  Yaowapa Sukpondma 3,  Narissara Lailerd 4,  Siribhorn Madla 5,  Somchai Sriwiriyajan 2,  Thidarath Rattanaburee 5,  Varomyalin Tipmanee 6,  Potchanapond Graidist 7
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand; The Excellent Research Laboratory of Cancer Molecular Biology, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand; Medical Technology Program, School of Allied Health Sciences, Walailak University, Thasala, Nakhonsithammarat, 80161, Thailand.
  • 2 Department of Pharmacology, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand.
  • 3 Department of Chemistry, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand.
  • 4 Department of Physiology, Faculty of Medicine, Chiang Mai University, Mueang Chiang Mai, Chiang Mai, 50200, Thailand.
  • 5 Department of Biomedical Sciences, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand; The Excellent Research Laboratory of Cancer Molecular Biology, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand.
  • 6 Department of Biomedical Sciences, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand.
  • 7 Department of Biomedical Sciences, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand; The Excellent Research Laboratory of Cancer Molecular Biology, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand. Electronic address: gpotchan@medicine.psu.ac.th.
PMID: 32619673 DOI: 10.1016/j.ejphar.2020.173311
Abstract

Natural and synthetic (-)-kusunokinin inhibited breast Cancer, colon Cancer and cholangiocarcinoma cells at the G2/M phase and induced Apoptosis. However, there is no report on the action and adverse effects of (-)-kusunokinin in animal models. In this study, we investigated the cytotoxic effect of (-)-kusunokinin from Piper nigrum on Cancer cells. NMU-induced rat mammary tumors, an ER positive breast Cancer model, were treated with (-)-kusunokinin. Proteins of interest related to cell cycle, angiogenesis, migration and signaling proteins were detected in tumor tissues. Results showed that (-)-kusunokinin exhibited strong cytotoxicity against breast, colon and lung Cancer cells and caused low toxicity against normal fibroblast cells. For in vivo study, 7.0 mg/kg and 14.0 mg/kg of (-)-kusunokinin reduced tumor growth without side effects on body weight, internal organs and bone marrow. Combination of (-)-kusunokinin with a low effective dose of doxorubicin significantly inhibited tumor growth and provoked cell death in Cancer tissues. Mechanistically, 14.0 mg/kg of (-)-kusunokinin decreased cell proliferation (c-Src, PI3K, Akt, p-Erk1/2 and c-Myc), cell cycle (E2f-1, cyclin B1 and CDK1), and metastasis (E-cadherin, MMP-2 and MMP-9) proteins in tumor tissues, which supports its Anticancer effect. We further confirmed the antimigration effect of (-)-kusunokinin; the results show that this compound inhibited breast Cancer cell (MCF-7) migration in a dose-dependent manner. In conclusion, the results suggest that 14 mg/kg of (-)-kusunokinin inhibited tumors through the reduction of signaling proteins and their downstream molecules. Therefore, (-)-kusunokinin becomes an intriguing candidate for Cancer treatment as it provides a strong potency in Cancer inhibition.

Keywords

(−)-Kusunokinin; Anticancer; Breast cancer; Piper nigrum; Signaling protein.

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