Ixabepilone: targeting βIII-tubulin expression in taxane-resistant malignancies

Abstract

Microtubule-targeting agents, such as taxanes and epothilones, block mitosis and cell proliferation by targeting the dynamics of the cytoskeleton. The taxanes are widely used for treatment of various malignancies, but primary and acquired resistance to chemotherapy remains a significant clinical concern. Class I, II, III, IV, and V B-tubulin isotypes are expressed in human tumors. Overexpression of the BIII-tubulin isotype is one mechanism that can render tumor cells resistant to taxanes. The relative expression of BIII-tubulin correlates with clinical outcomes in several tumor types, including breast cancer, non -small cell lung cancer, and ovarian cancer. A novel analogue of epothilone B, ixabepilone, has recently been approved in combination with capecitabine for the treatment of patients with anthracycline-and taxaneresistant locally advanced or metastatic breast cancer and as monotherapy in patients whose tumors are resistant or refractory to an anthracycline, a taxane, and capecitabine. The significant antitumor activity of ixabepilone in taxaneresistant tumors may be related to its preferential suppression of the dynamic instability of A/BIII-microtubules in cells expressing high levels of BIII-tubulin.

AMG 900, a Small-Molecule Inhibitor of Aurora Kinases, Potentiates the Activity of Microtubule-Targeting Agents in Human Metastatic Breast Cancer Models

“…3A). Interestingly, the bIII-tubulin overexpressing DU4475 cells also showed elevated expression of P-gp protein, which may represent a dual mechanism of resistance to taxanes (25,26). In preparation for future combination studies, we evaluated the cell-cycle effects of AMG 900, paclitaxel, and ixabepilone in the same set of breast cancer cell lines to determine single-agent potency.…”

Secreted Frizzled Related Protein 1 Modulates Taxane Resistance of Human Lung Adenocarcinoma

“…Tumor cells acquire resistance to taxanes through various mechanisms including alteration in tubulin dynamics, differences in β-tubulin isotype expression and upregulation of members of the ATP binding cassette transporters (ABC transporter family) in cancer cells (16,17). To better understand the molecular mechanisms involved in drug resistance of the LAD, SPC-A1/DTX and A549/ Taxol cell lines were established in our lab.…”

Paclitaxel resistance development is associated with biphasic changes in reactive oxygen species, mitochondrial membrane potential and autophagy with elevated energy production capacity in lung cancer cells: A chronological study

“…The IC 50 value for 48-h Tx treatment increased to 71 nM in case of 10 nM resistance cells (TxR10) in comparison to that of control A549 cells (whose IC 50 was 48 nM; Figure 1(b)). Moreover, gradual increase of expression of βIII tubulin, a marker for Tx resistance in lung cancer cells, 40,41 as well as MDR1 and MRP1 expressions were observed in course of resistance development (Figure 1(c)). …”