Targeting cancer stem cells with dietary phytochemical - Repositioned drug combinations

Abstract

The tumor microenvironment is complex with the cancer stem cell (CSC) as a member within its community. This population possesses the capacity to self-renew and to cause cellular heterogeneity of the tumor. CSCs are resistant to conventional anti-proliferative drugs. In order to be curative, it is imperative that CSCs must be eliminated by cancer therapy. A variety of dietary phytochemicals and repositioned drugs can act synergistically with conventional anti-cancer agents. In this review, we advocate the development of a novel approach, namely combination therapy by incorporating both phytochemicals and repositioned drugs to target CSCs. We cover select dietary phytochemicals (curcumin, resveratrol, EGCG, genistein) and repurposed drugs (metformin, niclosamide, thioridazine, chloroquine). Five of the eight (curcumin, resveratrol, EGCG, genistein, metformin) are listed in "The Halifax Project", that explores "the concept of a low-toxicity 'broad-spectrum' therapeutic approach that could simultaneously target many key pathways and mechanisms" [1]. For these compounds, we discuss their mechanisms of action, in which models their anti-CSC activities were identified, as well as advantages, challenges and potentials of combination therapy.

Flavonoids as Epigenetic Modulators for Prostate Cancer Prevention

“…Epigallocatechin-gallate (EGCG) is the most abundant (at least 50% of the total catechin content) and the most biologically active catechin present in green tea extracts. Many clinical studies have demonstrated the anti-proliferative, anti-oxidant, and anti-cancer effect of EGCG and, more generally, of a green tea catechins mixture [161], given pure or in combination with other natural compounds [162,163]. Although the anti-tumoral effects of EGCG have clearly been recognized, the molecular mechanism of action of catechins needs more investigation.…”

Phytochemicals based chemopreventive and chemotherapeutic strategies and modern technologies to overcome limitations for better clinical applications

“…Curcumin inhibits cancer development and progression by targeting the PI3K/AKT signaling pathway in prostate, lung, breast, and ovarian cancers (Yallapu et al, ; Hamzehzadeh, Atkin, Majeed, Butler, & Sahebkar, ; Jin, Qiao, Wang, Xu, & Shang, ; Wang et al, ; Yallapu et al, ; Yu et al, ). Curcumin has also gained much importance in the recent past due to its potential of targeting CSCs (Chan et al, ; Dandawate et al, ; Subramaniam et al, ).…”

“…The effectiveness of phytochemicals has also been found promising on cancer stem cells (CSCs) and has gained immense attention in the recent past for their therapeutic potential against drug-resistant cancers by targeting CSCs and associated signaling pathways (Dandawate, Subramaniam, Jensen, & Anant, 2016;Liskova et al, FIGURE 2 Structure of some common phytochemicals 2019; Oh, Hlatky, Jeong, & Kim, 2016;Subramaniam, Kaushik, Dandawate, & Anant, 2018). A combination of dietary phytochemicals and some repositioned drugs (e.g., metformin, niclosamide, and thioridazine) along with conventional chemotherapeutic drugs have been shown to induce synergistic effects in targeting CSCs (Chan, Chen, & Fong, 2018).…”

“…The effectiveness of phytochemicals has also been found promising on cancer stem cells (CSCs) and has gained immense attention in the recent past for their therapeutic potential against drug-resistant cancers by targeting CSCs and associated signaling pathways (Dandawate, Subramaniam, Jensen, & Anant, 2016;Liskova et al, FIGURE 2 Structure of some common phytochemicals 2019; Oh, Hlatky, Jeong, & Kim, 2016;Subramaniam, Kaushik, Dandawate, & Anant, 2018). A combination of dietary phytochemicals and some repositioned drugs (e.g., metformin, niclosamide, and thioridazine) along with conventional chemotherapeutic drugs have been shown to induce synergistic effects in targeting CSCs (Chan, Chen, & Fong, 2018). As shown in Figure 3, phytochemicals exert anticancer effects by targeting CSCs and multiple signaling pathways such as interfering with microtubules assembly, augmentation of cellular antioxidant and/or detoxification system, suppression of inflammation and tumor angiogenesis, inhibition of epithelial to mesenchymal transition, tumor invasion, metastasis, tumor cell metabolism, and induction of apoptosis, autophagy, epigenetic regulation, and so forth (Žiberna et al, 2017;Lee, Choi, & Kim, 2015;Manoharan, Panjamurthy, Balakrishnan, Vasudevan, & Vellaichamy, 2009).…”

Curcumin stimulates angiogenesis through VEGF and expression of HLA‐G in first‐trimester human placental trophoblasts

“…Curcumin (diferuloylmethane) isolated from the dried powder of rhizome of Curcuma longa Linn ( Zingiberaceae ) (Akbar et al, 2018), has been shown to have beneficial properties in vitro and in vivo studies (Akbar et al, 2018; Mokhtari‐Zaer et al, 2018). Curcumin modulates cell growth and inhibits angiogenesis in cancer cells (Fan et al, 2016; Huang et al, 2017; Chan et al, 2018). The anti‐cancer effects of curcumin are mediated partly via down‐regulation of angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and upregulation of expression of anti‐metastatic proteins and the tissue inhibitor of metalloprotease‐2 (TIMP2).…”