Repurposing of Fluvastatin as an Anticancer Agent against Breast Cancer Stem Cells via Encapsulation in a Hyaluronan-Conjugated Liposome

Abstract

Fluvastatin (FLUVA), which is a common anti-hypercholesterolemia drug, exhibits potential anticancer activity as it suppresses the proliferation, angiogenesis, and metastasis of breast cancer cells via inhibiting 3-hydroxy-methyl glutaryl-coenzyme A (HMG-CoA) reductase. In this study, hyaluronan-conjugated FLUVA-encapsulating liposomes (HA-L-FLUVA) were evaluated for their anticancer efficacy in vitro and in vivo. The particle size, zeta potential, and encapsulation efficiency of HA-L-FLUVA were 158.36 ± 1.78 nm, −24.85 ± 6.26 mV, and 35%, respectively. Growth inhibition of breast cancer stem cells (BCSCs) by HA-L-FLUVA was more effective than that by free FLUVA. The half maximal inhibitory concentration (IC50) values of FLUVA, L-FLVUA, and HA-L-FLUVA were 0.16, 0.17, and 0.09 μM, respectively. The in vivo anticancer effect of HA-L-FLUVA in combination with doxorubicin (DOX) was more effective than that of free FLUVA, free DOX, and HA-L-FLUVA. The longest survival of mice was achieved by treatment with FLUVA (15 mg/kg) and HA-L-FLUVA (15 mg/kg) + DOX (3 mg/kg), followed by HA-L-FLUVA (15 mg/kg), Dulbecco’s phosphate buffered saline, and DOX (3 mg/kg). No more than 10% body weight loss was observed in the mice injected with FLUVA, indicating that the drug was not toxic. Taken together, these results indicate that HA-L-FLUVA could serve as an effective anticancer drug by inhibiting the growth of both breast cancer cells and cancer stem cells.

An Overview of Antitumour Activity of Polysaccharides

“…Breast cancer stem cellxenografted mouse model [129] HA-coated silica/hydroxyapatite-DOX HA-coated inorganic nanoparticles CD44-targeted 4T1 tumor-bearing mice [130] HA-sclareol/poly-lacticco-glycolic acid HA-coated inorganic nanoparticles CD44-targeted, hydrophilic MCF-7 and MDA-MB468 cell lines [131] HA-coated camptothecin HA-coated inorganic nanoparticles CD44-targeted MDA-MB-231 cells [132] HA and poly-(N-εcarbobenzyloxy-Llysine)…”

Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance

“…Simvastatin induces glutathione (GSH)-mediated suppression of ABCG4 (which causes efflux of intracellular doxorubicin and cisplatin) levels, increasing the sensitivity of prostate cancer cells to doxorubicin or cisplatin and leading to the suppression of tumor growth and size without doxorubicin-induced cytotoxicity [ 98 ]. An in vivo tumor xenograft model of breast cancer showed that encapsulation of fluvastatin in a hyaluronan-conjugated liposome and administration with doxorubicin produced a potent anti-proliferative effect with the longest survival in mice [ 99 ]. Atorvastatin sensitizes the anti-cancer effect of doxorubicin and cisplatin in human osteosarcoma by suppressing matrix metalloprotease 2 (MMP2) induced by doxorubicin and cisplatin [ 100 ].…”