Phloridzin Docosahexaenoate Inhibits Spheroid Formation by Breast Cancer Stem Cells and Exhibits Cytotoxic Effects against Paclitaxel-Resistant Triple Negative Breast Cancer Cells

Abstract

The eradication of cancer stem cells (CSCs) is vital to successful cancer treatment and overall disease-free survival. CSCs are a sub-population of cells within a tumor that are defined by their capacity for continuous self-renewal and recapitulation of new tumors, demonstrated in vitro through spheroid formation. Flavonoids are a group of phytochemicals with potent anti-oxidant and anti-cancer properties. This paper explores the impact of the flavonoid precursor phloridzin (PZ) linked to the ω-3 fatty acid docosahexaenoate (DHA) on the growth of MCF-7 and paclitaxel-resistant MDA-MB-231-TXL breast cancer cell lines. Spheroid formation assays, acid phosphatase assays, and Western blotting were performed using MCF-7 cells, and the cell viability assays, Annexin-V-488/propidium iodide (PI) staining, and 7-aminoactinomycin D (7-AAD) assays were performed using MDA-MB-231-TXL cells. PZ-DHA significantly reduced spheroid formation, as well as the metabolic activity of MCF-7 breast cancer cells in vitro. Treatment with PZ-DHA also suppressed the metabolic activity of MDA-MB-231-TXL cells and led to apoptosis. PZ-DHA did not have an observable effect on the expression of the drug efflux transporters ATP-binding cassette super-family G member 2 (ABCG2) and multidrug resistance-associated protein 1 (MRP1). PZ-DHA is a potential treatment avenue for chemo-resistant breast cancer and a possible novel CSC therapy. Future pre-clinical studies should explore PZ-DHA as a chemo-preventative agent.

Phlorizin, an Important Glucoside: Research Progress on Its Biological Activity and Mechanism

“…Phlorizin docosahexaenoate, a novel fatty acid ester of plant polyphenols, inhibits the formation of spheroids in breast cancer stem cells and exhibits cytotoxic effects on paclitaxelresistant triple-negative breast cancer cells [80][81][82]. It can be seen that the acylated derivatives of phlorizin have good biological activity in anti-cancer.…”

Cancer Stem Cells from Definition to Detection and Targeted Drugs

“…Li et al synthesised derivatives of apigenin and found one-compound 15e-with strong activity (IC50 of 0.49 versus 44 microM of apigenin) against the growth of human renal carcinoma cells [203]. More recently, Fernando et al reported a fatty acid ester of phloridzin that inhibited spheroid formation by breast cancer cells in vitro [204]. The conjugate could also inhibit the metabolic activity and induce cell death of paclitaxel-resistant variants, while investigation of the effects on stemness markers at low concentrations is warranted [204].…”

“…More recently, Fernando et al reported a fatty acid ester of phloridzin that inhibited spheroid formation by breast cancer cells in vitro [204]. The conjugate could also inhibit the metabolic activity and induce cell death of paclitaxel-resistant variants, while investigation of the effects on stemness markers at low concentrations is warranted [204]. A synthetic analogue of genistein was also demonstrated to attenuate the expression of FoxM1 and other stemness features of gastric, ovarian, and lung cancer cells [164].…”