Flubendazole Enhances the Inhibitory Effect of Paclitaxel via HIF1α/PI3K/AKT Signaling Pathways in Breast Cancer

Abstract

Paclitaxel, a natural anticancer drug, is widely recognized and extensively utilized in the treatment of breast cancer (BC). However, it may lead to certain side effects or drug resistance. Fortunately, combination therapy with another anti-tumor agent has been explored as an option to improve the efficacy of paclitaxel in the treatment of BC. Herein, we first evaluated the synergistic effects of paclitaxel and flubendazole through combination index (CI) calculations. Secondly, flubendazole was demonstrated to synergize paclitaxel-mediated BC cell killing in vitro and in vivo. Moreover, we discovered that flubendazole could reverse the drug resistance of paclitaxel-resistant BC cells. Mechanistically, flubendazole was demonstrated to enhance the inhibitory effect of paclitaxel via HIF1α/PI3K/AKT signaling pathways. Collectively, our findings demonstrate the effectiveness of flubendazole in combination with paclitaxel for treating BC, providing an insight into exploiting more novel combination therapies for BC in the future.

Synergistic effects of epoxyazadiradione (EAD) and paclitaxel against triple‐negative breast cancer cells

“…The synergistic effects of paclitaxel and flubendazole have been demonstrated in breast cancer, both in vitro and in vivo. This combination could reverse the drug resistance induced by paclitaxel and enhance the inhibitory effect of paclitaxel via HIF1 HIF1α/PI3K/AKT signalling pathways [30]. The antifungal metabolite trichostatin A, the known inhibitor of mammalian histone deacetylase I and II, synergistically activates paclitaxel to induce cytotoxicity by suppressing ERK1/2 [31].…”

A novel signature integrated endoplasmic reticulum stress and apoptosis related genes to predict prognosis for breast cancer

“…Camilla T. et al [ 41 ] found that missense mutant p53 oncoproteins increase the synthesis of de novo serine/glycine synthesis and the intake of essential amino acids, which accelerates the development of breast cancer. In breast cancer, flubendazole increases the inhibitory effect of paclitaxel through the HIF1α/PI3K/AKT signaling pathways [ 42 ]. The reliability of our findings has been confirmed by these investigations.…”

Revitalizing Cancer Treatment: Exploring the Role of Drug Repurposing

“…Additionally, FLBZ exhibited the capability to reduce lung and liver metastasis by targeting angiogenesis by inhibiting STAT3 signaling and downregulating MMP-2 and MMP-9 expression [71]. FLBZ was demonstrated to sensitize BC cells resistant to PTX by targeting the HIFα-dependent PI3K/Akt pathway [72]. These studies recommend the repurposing of anthelmintic drugs, specifically ABZ, MBZ, and FLBZ, for clinical evaluation against breast cancer subtypes, with a particular emphasis on TNBC.…”