ReviewMitochondrial dysfunction in cancer chemoprevention by phytochemicals from dietary and medicinal plants
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.
Section snippets
Mitochondrial dysfunction and cancer
Mitochondrial function is not limited to ATP generation from oxidative phosphorylation (OXPHOS) but this organelle is implicated in numerous biochemical reactions [45]. Mitochondrial involvement in carcinogenesis has also been reviewed extensively [9], [21], [51]. Furthermore, this organelle is a target of cancer therapy because of its vital role in pro-death and pro-survival pathways [18], [64]. Mitochondrial dysfunction is also implicated in cancer initiation and progression [9]. Defects in
Inhibition of electron transport chain (ETC) by cancer chemopreventive phytochemicals
In this section, we review scientific evidence implicating inhibition of ETC by cancer chemopreventive phytochemicals shown in Fig. 1. PEITC and BITC are aromatic ITCs with a minor difference, whereas SFN is a thioalkyl type ITC compound. Several other naturally-occurring thioalkyl type ITCs have also been identified in plants but SFN is the best studied member of this subclass [16]. It is important to mention that SFN occurs naturally as an L-isomer but most studies have used synthetic racemic
Alteration of mitochondrial dynamics by BITC in breast cancer cells
Persistent fission and fusion of mitochondria is essential for their integrity and normal physiology [14]. A role for mitochondrial dynamics in regulation of apoptosis has been suggested [6], [57]. Generally speaking, mitochondrial fusion inhibits apoptosis and mitochondrial fission promotes release of apoptogenic factors to trigger apoptotic cell death [7], [4]. In cells committed to apoptosis, the normal filamentous network of mitochondria is fragmented (punctate and spherical) due to
Conclusions and gaps in knowledge
Even though the experimental evidence for ETC inhibition by the highlighted cancer chemopreventive phytochemicals is compelling, the underlying mechanism is still not fully resolved. One possibility for ETC inhibition by ITCs and WA may entail covalent modification of sulfhydryl groups in critical cysteine in complex III subunits owing to their electrophilic nature. It is also plausible that the agents covered in this review and possibly other cancer chemopreventive phytochemicals cause
Conflict of interest
None of the authors declares any conflict of interest.
Funding
The research cited from the senior author’s laboratory was supported by United States Public Health Services grants CA101753, CA115498, CA129347, and CA142604 awarded by the National Cancer Institute- National Institutes of Health.
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