YM155 Restores the Effect of Imatinib in Imatinib-Resistant Chronic Myeloid Leukemia Cell Lines

Title:YM155 Restores the Effect of Imatinib in Imatinib-Resistant Chronic Myeloid Leukemia Cell Lines

Volume: 26

Author(s): Belal A. Al-Husein*, Mohammad A. Bani-Ahmad, Rand M. Nofal and Mohammad A.Y. Alqudah

Affiliation:

• Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, 22110, Jordan

Keywords: Chronic myelogenous leukemia, BCR-ABL, imatinib, imatinib resistance, surviving, survivin inhibitor, YM155, BIRC5.

Abstract:

Introduction: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the Philadelphia chromosome. Imatinib is considered the standard therapy for CML due to its targeted action against the BCR::ABL1 tyrosine kinase. However, resistance to imatinib often emerges, particularly in the advanced stages of CML. One factor associated with imatinib resistance is the overexpression of survivin (baculoviral IAP repeat-containing 5, BIRC5). YM155 is an innovative survivin inhibitor that suppresses survivin expression and triggers apoptosis. Combination therapy is a strategy used to enhance the effectiveness of cancer treatment and overcome resistance.

Methods: Our study explored the in vitro anticancer effects of YM155 as monotherapy and as a combination therapy with imatinib on imatinib-sensitive (K-562) and imatinib-resistant (K562-r) BCR::ABL1+ CML cell lines. Results: Survivin inhibition significantly reduced pro-liferation in both K-562 and K562-r cells. Combination therapy with YM155 and imatinib produced a synergistic effect. In K562-r cells (imatinib IC50 = 6 μM), the combination reduced the IC50 by 6.2-fold. In K-562 cells, the IC50 decreased by 16.3-fold. Both monotherapy and combination therapy markedly increased apoptosis, with combination therapy inducing significantly greater apoptosis. The combination also downregulated survivin and BCR::ABL1 tyrosine kinase expression and significantly reduced BCR::ABL1 mRNA levels.

Conclusion: YM155 enhances imatinib’s efficacy against both sensitive and resistant CML cells, overcoming resistance through synergistic inhibition of proliferation, increased apoptosis, and suppression of survivin and BCR::ABL1 expression. These results support further investigation of YM155-Imatinib combination therapy as a potential strategy for resistant CML.

Cite this article as:

Al-Husein A. Belal*, Bani-Ahmad A. Mohammad, Nofal M. Rand and Alqudah A.Y. Mohammad, YM155 Restores the Effect of Imatinib in Imatinib-Resistant Chronic Myeloid Leukemia Cell Lines, Current Cancer Drug Targets 2026; 26 () . https://dx.doi.org/10.2174/0115680096402329251002224513