Cancer Cell Int. 2019 Mar 08;19:54. doi: 10.1186/s12935-019-0769-2. eCollection 2019.
Combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator AMP-activated kinase.
Cancer cell international
Belén G Sánchez, Alicia Bort, Pedro A Mateos-Gómez, Nieves Rodríguez-Henche, Inés Díaz-Laviada
Affiliations
Affiliations
- 1Department of Systems Biology, Biochemistry and Molecular Biology Unit, School of Medicine and Health Sciences, Alcala University, Alcalá de Henares, Ctra A-2 Km 32., 28871 Madrid, Spain.
- 2Chemical Research Institute "Andrés M. del Río" (IQAR), Alcalá University, Alcalá de Henares, 28871 Madrid, Spain.
PMID: 30899201
PMCID: PMC6408806 DOI: 10.1186/s12935-019-0769-2
Abstract
BACKGROUND: Current chemotherapy for castration-resistant prostate cancer is established on taxane-based compounds like docetaxel. However, eventually, the development of toxic side effects and resistance limits the therapeutic benefit being the major concern in the treatment of prostate cancer. Combination therapies in many cases, enhance drug efficacy and delay the appearance of undesired effects, representing an important option for the treatment of castration-resistant prostate cancer. In this study, we tested the efficacy of the combination of docetaxel and capsaicin, the pungent ingredient of hot chili peppers, on prostate cancer cells proliferation.
METHODS: Prostate cancer LNCaP and PC3 cell lines were used in this study. Levels of total and phosphorylated forms of Akt, mTOR, S6, LKB1, AMPK and ACC were determined by Western blot. AMPK, LKB1 and Akt knock down was performed by siRNA. PTEN was overexpressed by transient transfection with plasmids. Xenograft prostate tumors were induced in nude mice and treatments (docetaxel and capsaicin) were administered intraperitoneally. Statistical analyses were performed with GraphPad software. Combination index was calculated with Compusyn software.
RESULTS: Docetaxel and capsaicin synergistically inhibited the growth of LNCaP and PC3 cells, with a combination index lower than 1 for most of the combinations tested. Co-treatment with docetaxel and capsaicin notably decreased Akt and its downstream targets mTOR and S6 phosphorylation. Overexpression of PTEN phosphatase abrogated the synergistic antiproliferative effect of docetaxel and capsaicin. The combined treatment also increased the phosphorylation of AMP-activated kinase (AMPK) and the phosphorylation of its substrate ACC. In addition, pharmacological inhibition of AMPK with dorsomorphin (compound C) as well as knock down by siRNA of AMPK or its upstream kinase LKB1, abolished the synergy of docetaxel and capsaicin. Mechanistically, we showed that the synergistic anti-proliferative effect may be attributed to two independent effects: Inhibition of the PI3K/Akt/mTOR signaling pathway by one side, and AMPK activation by the other. In vivo experiments confirmed the synergistic effects of docetaxel and capsaicin in reducing the tumor growth of PC3 cells.
CONCLUSION: Combination of docetaxel and capsaicin represents a therapeutically relevant approach for the treatment of Prostate Cancer.
Keywords: AMPK; Capsaicin; Docetaxel; LNCaP cells; PC3 cells; Prostate cancer
References
- J Cell Sci. 2004 Nov 1;117(Pt 23):5479-87 - PubMed
- Pharmacol Rev. 2006 Sep;58(3):621-81 - PubMed
- Anesth Analg. 2008 Aug;107(2):507-24 - PubMed
- Cancer Res. 2010 Jan 15;70(2):440-6 - PubMed
- Int J Oncol. 2012 May;40(5):1683-90 - PubMed
- Crit Rev Food Sci Nutr. 2012;52(5):373-81 - PubMed
- Drugs. 2012 Jul 30;72(11):1559-77 - PubMed
- J Urol. 2014 Jan;191(1):227-34 - PubMed
- J Pharmacol Pharmacother. 2013 Oct;4(4):303-6 - PubMed
- Oncogene. 2014 Oct 23;33(43):5053-64 - PubMed
- Drug Resist Updat. 2014 Apr;17(1-2):13-23 - PubMed
- Prog Drug Res. 2014;68:181-208 - PubMed
- Clin Transl Oncol. 2015 Feb;17(2):145-51 - PubMed
- J Control Release. 2014 Dec 28;196:96-105 - PubMed
- PLoS One. 2015 May 01;10(5):e0121538 - PubMed
- Nat Commun. 2015 Jul 17;6:7769 - PubMed
- Phytother Res. 2015 Nov;29(11):1828-36 - PubMed
- Mol Med Rep. 2016 Jan;13(1):881-7 - PubMed
- Cancer Epidemiol Biomarkers Prev. 2016 Jan;25(1):16-27 - PubMed
- Cancer Med. 2016 Jun;5(6):1251-8 - PubMed
- Anticancer Res. 2016 Mar;36(3):837-43 - PubMed
- Trends Pharmacol Sci. 2016 Jun;37(6):451-462 - PubMed
- Mol Cancer. 2016 Nov 10;15(1):70 - PubMed
- J Urol. 2017 Apr;197(4):1068-1075 - PubMed
- CA Cancer J Clin. 2017 Jan;67(1):7-30 - PubMed
- Biochem Pharmacol. 2017 Apr 1;129:54-66 - PubMed
- Prostate. 2017 May;77(6):654-671 - PubMed
- Oncotarget. 2017 Jun 6;8(23):38022-38043 - PubMed
- Biosci Rep. 2017 May 11;37(3):null - PubMed
- Curr Urol Rep. 2017 Jun;18(6):46 - PubMed
- Int J Med Sci. 2017 Apr 7;14(4):356-366 - PubMed
- Oncotarget. 2017 Apr 27;8(34):57733-57754 - PubMed
- Oncotarget. 2017 Sep 23;8(50):87684-87698 - PubMed
- Cell Metab. 2018 Feb 6;27(2):299-313 - PubMed
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