Methyl-β-cyclodextrin, an actin depolymerizer augments the antiproliferative potential of microtubule-targeting agents

The effect of Methyl BCD (RAMEB) on cytoskeleton was studied. It was found that disassembling the actin network did not perturb the microtubules. Actin network and microtubules provide the structure and shape of cytoskeleton and have important role in several cell functions. Using traction force microscopy, Methyl BCD-treatment was found to reduce traction force and stiffness of HeLa cells. This treatment also enhanced the permeability of the cell membrane and uptake of small molecules such as vinblastin, crocin and curcumin. It was assumed that depolymerization of actin network can be the cause of these phenomena. The combined effect of actin depolymerization by Methyl BCD and microtubule perturbation by microtubule-targeting agents (MTAs), such as vinblastin, crocine and taxol, on traction force and de-adhesion kinetics of the cells was studied.

The antiproliferative activity of vinblastine, crocin and taxol against HeLa cells is potentiated by pre-treatment with Methyl BCD. Vinblastine, taxol and crocin inhibited the proliferation of Methyl BCD-treated HeLa cells with an IC₅₀ value of 1.9 ± 0.2 nM, 2.7 ± 0.3 nM and 0.6 ± 0.2 µM, respectively, which are significantly (p < 0.01) lower than vinblastine, taxol and crocin alone 4.2 ± 0.1 nM, 7 ± 0.3 nM and 1.5 ± 0.1 µM, respectively. This drug combination was successfully applied also on multi-drug resistant mouse breast mammary carcinoma (EMT/AR1) cells. The IC₅₀ value of vinblastine was reduced from 3.7 ± 0.6 µM to 1 ± 0.05 µM (p < 0.01) and that of taxol from 1.2 ± 0.03 µM to 0.5 ± 0.02 µM (p < 0.01) indicating that Methyl BCD can sensitize drug-resistant cells towards MTAs.

Methyl BCD-mediated actin depolymerization increases the intracellular accumulation of microtubule-targeting agents (MTAs) by ~50% with respect to the untreated cells. As Methyl BCD treatment enhances the intracellular concentration of drugs, it was hypothesized that the Methyl BCD-sensitized cancer cells could be effectively killed by low doses of MTAs. Combined use of Methyl BCD and MTAs synergistically inhibits the proliferation of tumor cells. These results indicate the potential use of Methyl BCD in combination with MTAs for cancer chemotherapy and suggest that targeting both actin and microtubules simultaneously may be a useful strategy for cancer therapy.

Mundhara, N., Majumder, A., Panda, D. Scientific Reports 9, Article number: 7638 (2019) DOI: https://doi.org/10.1038/s41598-019-43947-4