A novel synthetic microtubule inhibitor exerts antiproliferative effects in multidrug resistant cancer cells and cancer stem cells

Abstract

The success of cancer chemotherapy is limited by multidrug resistance (MDR), which is mainly caused by P-glycoprotein (P-gp) overexpression. In the present study, we describe a novel microtubule inhibitor, 5-(N-methylmaleimid-3-yl)-chromone (SPC-160002), that can be used to overcome MDR. A synthetic chromone derivative, SPC-160002, showed a broad spectrum of anti-proliferative effects on various human cancer cells without affecting P-gp expression and its drug efflux function. Treatment with SPC-160002 arrested the cell cycle at the M phase, as evidenced using fluorescence-activated cell sorting analysis, and increased the levels of mitotic marker proteins, including cyclin B, pS10-H3, and chromosomal passenger complex. This mitotic arrest by SPC-160002 was mediated by promoting and stabilizing microtubule polymerization, similar to the mechanism observed in case of taxane-based drugs. Furthermore, SPC-160002 suppressed the growth and sphere-forming activity of cancer stem cells. Our data herein strongly suggest that SPC-160002, a novel microtubule inhibitor, can be used to overcome MDR and can serve as an attractive candidate for anticancer drugs.

PRMT7 Inhibitor SGC8158 Enhances Doxorubicin-Induced DNA Damage and Its Cytotoxicity

“…The molecular mechanisms underlying how PRMT7 regulates p21 turnover remain to be explored. The KBV20C cells, a well-characterized MDR cancer cell line, are derived from KB cells and are resistant to various chemotherapeutic agents, including vincristine, paclitaxel, and doxorubicin [ 36 , 37 , 38 ]. Since MDR has been considered a major hurdle for successful cancer therapy [ 39 , 40 ], it is noteworthy that SGC8158 is also effective in MDR cancer cells, providing an important clue in developing strategies to overcome MDR.…”

“…All cell lines were obtained from American Type Culture Collection (ATCC; Manassas, VA, USA). Multidrug-resistant KBV20C cells were derived from KB cells and cultured with 20 nM vincristine under growth conditions to preserve MDR characteristics, as described previously [ 36 , 37 ]. All the cells were maintained at 37 °C under 5% CO 2 in a humidified chamber.…”

Repositioning study of flubendazole for treating lung cancer and meningoencephalitis using an oral lipid nanosystem

“…It was hypothesized that the interaction between the microtubule and this group occur by the Michaeltype addition reaction on the sulfhydryl-rich heterodimer site of tubulin. Although the potency of SPC-16002 is weaker than paclitaxel, this is a novel microtubule-targeting drug for several human cancer cells, including MDR cancer cells(Park et al, 2021).Another elegant agent aiming to overcome drug resistance in diverse cancer cells is the peptide-based rotor molecule, driven by the multicomponent-targeting feature of molecular selfassembly (MSA). The synthesized MSA is an environmentally responsive molecule that can selfadjust morphologically in return for the variations of pH and viscosity during Golgi-endosome trafficking.…”