B III Tubulin Disulfide Bonds and Drug Resistance: A Novel Approach to the Treatment of Breast Cancer

摘要

Tubulin, a potential target for chemotherapy, plays an important role in different cellular functions including mitosis and cell division. Tubulin consists of mainly alpha and beta subunits: each subunit exists in several isoforms. The distribution and expression of beta- isoforms differ from tissue to tissue: beta-II and beta-IV are ubiquitously expressed while beta-III expression is restricted to neurons and cancer cells. Moreover, alpha-beta-III has least affinity for anti-tubulin drugs compared to alpha-beta-II and alpha- beta-III tubulin. In this study, we correlated the expression of beta-III tubulin and oxidative stress related to drug resistance in cancer cells. We have established a taxol-resistant BT474 breast cancer cell line (IC50=0.97 nM) from the taxol-sensitive line of BT454 (1C50=0.5 nM). We found that taxol-resistant BT454 cell line experienced higher oxidative stress compared to its sensitive line and the expression of beta-III tubulin was also found significantly elevated in drug-resistant cells. However, the expression of actin and beta-II tubulin remained unchanged. These data therefore, strongly suggest that selective elevation of expression of specific beta-III-tubulin cause development of drug resistance in breast cancer cells and the elevated level of formation of reactive oxygen species might be directly related to drug resistance.