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.

Introduction

Practicality and promise of cancer chemoprevention is demonstrated by clinical integration of selective estrogen receptor modulators and aromatase inhibitors for breast cancer and human papilloma virus vaccines for cervical cancer [17], [22], [42]. Small molecule phytochemicals present in dietary and medicinal plants also appear promising for cancer chemoprevention [58], [48], [55]. Cancer chemoprevention research on phytochemicals derived from the dietary plants was originally inspired by cues from the population-based epidemiological studies [61], [32], [23]. More recently, the scientific community has witnessed a surge in research focused on identification of cancer chemopreventive phytochemicals from medicinal plants [20], [59], [62]. Isothiocyanates (ITCs) from cruciferous vegetables (e.g., watercress, broccoli, mustard, and so forth), which are naturally stored as glucosinolates in these plants, have been widely studied for cancer chemoprevention using preclinical models [29], [55]. Examples of well-characterized cancer chemopreventive ITCs include phenethyl isothiocyanate (PEITC) from watercress, benzyl isothiocyanate (BITC) from garden cress, and sulforaphane (SFN) from broccoli [48], [55], [53]. All of these ITCs have shown in vivo cancer chemopreventive activity in rodent models [48], [55], [53]. Even though the evidence for cancer chemopreventive activity of ITCs in humans is still lacking, PEITC and SFN have entered clinical arena to determine their safety, bioavailability, and biological activity [12], [71]. Similarly, the preclinical evidence for cancer chemoprevention by some phytochemicals isolated from medicinal plants is quite persuasive. Examples of promising cancer chemopreventative phytochemicals isolated from medicinal plants include withaferin A (WA) from Withania somnifera and honokiol (HNK) from Magnolia officinalis [2], [62]. Evidence continues to accumulate to suggest that mitochondrial dysfunction is a critical event in cancer chemoprevention by ITCs, WA, and HNK. The net result of mitochondrial dysfunction triggered by these phytochemicals in cancer cells is apoptotic death that is mediated by generation of reactive oxygen species (ROS) [55], [53], [62]. The mechanisms by which these chemicals cause generation of ROS and the underlying pathways in cell death induction have been reviewed extensively by us and others, and therefore, are not covered in this article [1], [55], [53], [27], [62]. The primary focus of this perspective is to discuss experimental evidence pointing to mitochondrial dysfunction as a critical event leading to generation of ROS and eventual cancer cell death by promising phytochemicals. Gaps in our knowledge and unanswered questions pertaining to the mitochondrial dysfunction in cancer chemopreventive mechanisms for selected phytochemicals (ITCs, WA, and HNK) are also highlighted.