Histone deacetylase inhibitory activity of hydroxycapsaicin, a synthetic derivative of capsaicin, and its cytotoxic effects against human colon cancer cell lines

Abstract

Capsaicin possesses cytotoxic/anticancer activity and shares some common structural features, including a benzene ring and a long hydrophobic carbon tail, with the histone deacetylase (HDAC) inhibitors trichostatin A and suberoylanilide hydroxamic acid. The aims of this study were to investigate HDAC inhibitory and cytotoxic activities of a synthetic derivative of capsaicin, hydroxycapsaicin (6-hydroxy-N-(4-hydroxy-3-methoxybenzyl)-8-methylnonenamide), in colon cancer cell lines. Hydroxycapsaicin inhibited HDAC activity in vitro (IC 50 = 72 µM) much more effectively than the prototype capsaicin (IC 50 > 13.1 mM) and also exhibited HDAC inhibitory activity in human cells (HeLa cells). MTT assay demonstrated that hydroxycapsaicin was less toxic than capsaicin against both cancer and noncancer cells; however, hydroxycapsaicin, with greater HDAC inhibitory activity, was more effective than capsaicin at inducing apoptosis in colon cancer cell lines, especially in HCT116 cells. Hydroxycapsaicin appeared to induce less apoptotic cell death than capsaicin in Vero cells. Moreover, only hydroxycapsaicin induced S-phase cell-cycle arrest in both HT29 and HCT116 cells. The current study demonstrates that hydroxycapsaicin can act as a novel HDAC inhibitor, which would lead to a promising strategy for the development of safe and effective chemotherapeutic drugs from the abundant natural capsaicin of chili pepper.

Four New Anthraquinones with Histone Deacetylase Inhibitory Activity from Ventilago denticulata Roots

“…The MTT reduction assay was performed with non-cancer (Vero), human cervical cancer (HeLa), human lung carcinoma (A549) and human breast adenocarcinoma cancer (MCF-7) cell lines according to the method previously described [ 33 , 34 , 35 ]. Briefly, cells were seeded in a 96-well plate and incubated for 24 h. The cells were treated with the selected compounds and incubated at 37 °C in CO 2 for 24 h, 48 h, and 72 h. After incubation, the culture medium was exchanged with 110 μL of MTT (0.5 mg/mL in PBS medium) and incubated for 2 h. The amount of MTT formazan product was determined after dissolved in DMSO by measuring its absorbance with a microplate reader (Bio-Rad Laboratories, USA) at a test wavelength of 550 nm and a reference wavelength of 655 nm.…”

Capsicum annuum L. and its bioactive constituents: A critical review of a traditional culinary spice in terms of its modern pharmacological potentials with toxicological issues

“…Lee, Krisanapun, and Baek (2010) reported that capsaicin inhibited the growth of human lung cancer and colorectal cancer cells by up‐regulating the NAG‐1 gene expression and binding of C/EBP β with glycogen synthase kinase 3 β (GSK3 β ), and thus activated the transcription factor 3 (ATF3) and helped in inhibition of the GSK3 β and Protein Kinase C pathways. Capsaicin and its derivative hydroxycapsaicin were observed for potential cytotoxic histone deacetylase inhibitory activity by inducing S‐phase cell cycle arrest in both HT29 and HCT116 colon cancer cells (Senawong, Wongphakham, Saiwichai, Phaosiri, & Kumboonma, 2015). The carotenoids namely capsanthin, capsanthin 3′‐ester, capsanthin 3,3′‐diester, capsorubin, capsorbin diester, capsanthin 3,6‐epoxide, and cucurbitaxanthin A‐3′ester exhibited significant in vitro antitumor activity on Epstein–Barr virus early antigen (EBV‐EA) activation induced by 12‐ O ‐tetradecanoylphorbol‐13‐acetate (TPA) as a tumor promoter.…”

“…reported that capsaicin inhibited the growth of human lung cancer and colorectal cancer cells by up-regulating the NAG-1 gene expression and binding of C/EBPβ with glycogen synthase kinase 3β (GSK3β), and thus activated the transcription factor 3 (ATF3) and helped in inhibition of the GSK3β and Protein Kinase C pathways. Capsaicin and its derivative hydroxycapsaicin were observed for potential cytotoxic histone deacetylase inhibitory activity by inducing S-phase cell cycle arrest in both HT29 and HCT116 colon cancer cells(Senawong, Wongphakham, Saiwichai, Phaosiri, & Kumboonma, 2015). The carotenoids namely capsanthin, capsanthin 3 0 -ester, capsanthin 3,3 0 -diester, capsorubin, capsorbin diester, capsanthin 3,6-epoxide, and cucurbitaxanthin A-3 0 ester exhibited significant in vitro antitumor activity on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) as a tumor promoter.Out of that carotenoids namely capsanthin, capsanthin 3 0 -ester, and capsanthin 3,3 0 -diester exhibited potent in vivo antitumor-promoting activity by mouse skin two-stage carcinogenesis assay through 7,12-dimethylbenz[α]anthracene as an initiator and TPA as a promoter(Maoka, Mochida, et al, 2001).The anticancer potentials of C. annuum and capsaicin are summarized in Figure 7.…”

In vitro anti-proliferative activity of selected nutraceutical compounds in human cancer cell lines

“…Its highest cytotoxicity activity was exerted against p53 knockout HCT116 cell line (IC50: 19.67 µM), indicating these types of cells to be more sensitive to capsaicin than their corresponding p53 wild type HCT116 cells. A study by Senawong et al [ 25 ] demonstrated the anti-proliferative activity of capsaicin without cell-cycle arrest property against HCT 116 cells. Furthermore, it was shown that pepper seed extract, at a concentration of 500 µg/ml, exhibited greater anti-proliferative activity (96.8%) and increased apoptotic cell population by 2.2-fold in HCT 116 cell line [ 26 ].…”