Novel strategies targeting cancer stem cells through phytochemicals and their analogs

Abstract

Cancer stem cells (CSCs) are cells that exist within a tumor with a capacity of self-renewal and an ability to differentiate, giving rise to heterogeneous populations of cancer cells. These cells are increasingly being implicated in resistance to conventional therapeutics and have also been implicated in tumor recurrence. Several cellular signaling pathways including Notch, Wnt, phosphoinositide-3-kinase-Akt-mammalian target of rapamycin pathways, and known markers such as CD44, CD133, CD166, ALDH, etc. have been associated with CSCs. Here, we have reviewed our current understanding of self-renewal pathways and factors that help in the survival of CSCs with special emphasis on those that have been documented to be modulated by well characterized natural agents such as curcumin, sulforaphane, resveratrol, genistein, and epigallocatechin gallate. With the inclusion of a novel derivative of curcumin, CDF, we showcase how natural agents can be effectively modified to increase their efficacy, particularly against CSCs. We hope that this article will generate interest among researchers for further mechanistic and clinical studies exploiting the cancer preventive and therapeutic role of nutraceuticals by targeted elimination of CSCs.

Keywords: CDF; Cancer stem cells; EMT; Notch; Phytochemicals.

Fig. 1

Structures of phytochemicals that target CSCs

Fig. 2

Markers of cancer stem cell populations that have been shown to be modulated by phytochemicals. A number of cell surface as well as cytosolic markers have been associated with CSC phenotype. Accumulating evidence suggests that the individual populations enriched for the proposed CSC markers are sensitive to treatment with various phytochemicals

Fig. 3

Several key factors/signaling pathways in CSCs that are targets of phytochemicals. Notch signaling pathway activation results in cleavage of Notch by γ-secretase into Notch intracellular domain (NICD) that translocates to nucleus, a process that is known to be inhibited by multiple phytochemicals. Receptor tyrosine kinases (RTKs), such as PDGFR, IGFR, EGFR etc., activate PI3K–Akt–mTOR signaling pathway, and this pathway is also known to be regulated by phytochemicals at different steps. Binding of wnt ligand to its receptor Frizzled activates Dishevelled (DSH) leading to attenuation of GSK-3β-mediated repression of β-catenin. β-Catenin also translocates to nucleus resulting in induction of downstream signaling molecules, and this pathway is modulated by phytochemicals as well. Inhibition of these multiple signaling pathways represents a mechanism by which phytochemicals influence the phenotype of CSCs