Mitochondrial dysfunction in cancer chemoprevention by phytochemicals from dietary and medicinal plants

Abstract

Cancer chemoprevention, a scientific term coined by Dr. Sporn in the late seventies, implies use of natural or synthetic chemicals to block, delay or reverse carcinogenesis. Phytochemicals derived from edible and medicinal plants have been studied rather extensively for cancer chemoprevention using preclinical models in the past few decades. Nevertheless, some of these agents (e.g., isothiocyanates from cruciferous vegetables like broccoli and watercress) have already entered into clinical investigations. Examples of widely studied and highly promising phytochemicals from edible and medicinal plants include cruciferous vegetable constituents (phenethyl isothiocyanate, benzyl isothiocyanate, and sulforaphane), withaferin A (WA) derived from a medicinal plant (Withania somnifera) used heavily in Asia, and an oriental medicine plant component honokiol (HNK). An interesting feature of these structurally-diverse phytochemicals is that they target mitochondria to provoke cancer cell-selective death program. Mechanisms underlying cell death induction by commonly studied phytochemicals have been discussed rather extensively and thus are not covered in this review article. Instead, the primary focus of this perspective is to discuss experimental evidence pointing to mitochondrial dysfunction in cancer chemoprevention by promising phytochemicals.

Keywords: Chemoprevention; Electron transport chain; Mitochondrial dynamics; Mitochondrial dysfunction; Phytochemicals.

Figure 1

Molecular structures of the cancer chemopreventive phytochemicals highlighted in this article.

Figure 2

Mechanistic summary of mitochondria-mediated apoptosis induction by PEITC based on our own findings in prostate cancer cells (Xiao et al. 2010).

Figure 3

Inhibition of OXPHOS by SFN in LNCaP human prostate cancer cell line. (A-B) Representative pharmacologic profiling of oxygen consumption rate (OCR), indicative of OXPHOS, in LNCaP cells treated with DMSO (control) or the indicated doses of SFN for 6 hours (A) or 9 hours (B) through real-time measurements using the Seahorse Bioscience XF24 Extracellular Flux Analyzer. After measurement of basal oxygen consumption, the cells were treated with oligomycin (“O”, 1 μM), FCCP (“F”, 0.3 μM), 2-deoxyglucose (“2DG”, 100 mM), and rotenone (“R”, 1 μM) as indicated. Results shown are mean ± SD (n = 3). (C-D) Basal OCR level in LNCaP cells treated with DMSO (control) or indicated doses of SFN for 6 hours (C) or 9 hours (D). (E-F) FCCP-activated OCR level in LNCaP cells treated with DMSO (control) or the indicated doses of SFN for 6 hours (E) or 9 hours (F). (G-H) Total reserve capacity in LNCaP cells treated with DMSO (control) or the indicated doses of SFN for 6 hours (G) or 9 hours (H). Combined results (C-H) from three independent experiments are shown as mean ± SD (n = 13~14). *Statistically significant compared to DMSO-treated control by one-way ANOVA followed by Dunnett’s adjustment.