No abstract

Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder characterized by the presence of the Philadelphia chromosome which resulted from the reciprocal translocation between chromosomes 9 and 22. The pathogenesis of CML involves the constitutive activation of the BCR-ABL tyrosine kinase, which governs malignant disease by activating multiple signal transduction pathways. The BCR-ABL kinase inhibitor, imatinib, is the front-line treatment for CML, but the emergence of imatinib resistance and other tyrosine kinase inhibitors (TKIs) has called attention for additional resistance mechanisms and has led to the search for alternative drug treatments. In this paper, we discuss our current understanding of mechanisms, related or unrelated to BCR-ABL, which have been shown to account for chemoresistance and treatment failure. We focus on the potential role of the influx and efflux transporters, the inhibitor of apoptosis proteins, and transcription factor-mediated signals as feasible molecular targets to overcome the development of TKIs resistance in CML.

Abstract. resistance to tyrosine-kinase inhibitors is a serious problem in the treatment of chronic myeloid leukemia (cMl). Using Western blot, real-time qRT-PCR and flow cytometry, we investigated the expression of survivin, Smac/DIABLO and P-glycoprotein (Pgp) in patients with CML. Survivin overexpression has been associated with cancer progression, multidrug resistance, poor prognosis and short survival in several types of neoplasms including hematological malignancies. In this work, survivin expression was significantly elevated in late, in contrast to early, chronic phase CML (p=0.044). Patients with high or intermediate prognostic Sokal score presented higher survivin levels (p=0.012), as well as Smac/DIABLO levels (p=0.009) compared to low Sokal score. The strong correlation between survivin and Pgp expression in late (p=0.018), but not in early (p=0.5) chronic phase of cMl, suggests that this association may play a biological role in late cMl phase and may offer an important target for the development of new therapies.

Acute myeloid leukemia (AML) is a complex hematological disorder characterized by blockage of differentiation and high proliferation rates of myeloid progenitors. Anthracycline and cytarabine-based therapy has remained the standard treatment for AML over the last four decades. Although this treatment strategy has increased survival rates, patients often develop resistance to these drugs. Despite efforts to understand the mechanisms underlying cytarabine resistance, there have been few advances in the field. The present study developed an in vitro AML cell line model resistant to cytarabine (HL-60R), and identified chromosomal aberrations by karyotype evaluation and potential molecular mechanisms underlying chemoresistance. Cytarabine decreased cell viability, as determined by MTT assay, and induced cell death and cell cycle arrest in the parental HL-60 cell line, as revealed by Annexin V/propidium iodide (PI) staining and PI DNA incorporation, respectively, whereas no change was observed in the HL-60R cell line. In addition, the HL-60R cell line exhibited a higher tumorigenic capacity in vivo compared with the parental cell line. Notably, no reduction in tumor volume was detected in mice treated with cytarabine and inoculated with HL-60R cells. In addition, western blotting revealed that the protein expression levels of Bcl-2, X-linked inhibitor of apoptosis protein (XIAP) and c-Myc were upregulated in HL-60R cells compared with those in HL-60 cells, along with predominant nuclear localization of the p50 and p65 subunits of NF-κB in HL-60R cells. Furthermore, the antitumor effect of LQB-118 pterocarpanquinone was investigated; this compound induced apoptosis, a reduction in cell viability and a decrease in XIAP expression in cytarabine-resistant cells. Taken together, these data indicated that acquired cytarabine resistance in AML was a multifactorial process, involving chromosomal aberrations, and differential expression of apoptosis and cell proliferation signaling pathways. Furthermore, LQB-118 could be a potential alternative therapeutic approach to treat cytarabine-resistant leukemia cells.

Osteopontin (OPN) is upregulated in several types of tumor and has been associated with chemoresistance. However, the contribution of OPN splicing isoforms (OPN-SIs) to chemoresistance requires further investigation. The present study aimed to evaluate the expression patterns of each tested OPN-SI in cisplatin (CDDP)-resistant ovarian carcinoma cell lines, focusing on the role of the OPN-c isoform (OPNc) in drug resistance. ACRP ovarian cancer cells resistant to CDDP, as well as their parental cell line A2780, were used. Analyses of the transcriptional expression of OPN-SIs, epithelial-mesenchymal transition (EMT) markers and EMT-related cytokines were performed using reverse transcription-quantitative PCR. OPNc was silenced in ACRP cells using anti-OPNc DNA oligomers and stably overexpressed by transfecting A2780 cells with a mammalian expression vector containing the full length OPNc cDNA. Functional assays were performed to determine cell proliferation, viability and colony formation. The results demonstrated that among the three tested OPN-SIs, OPNc was the most upregulated transcript in the ACRP cells compared with the parental A2780 cells. In addition, the expression levels of P-glycoprotein multidrug transporter were upregulated in CDDP-resistant ACRP cells compared with those in A2780 cells. OPNc knockdown sensitized ACRP cells to CDDP treatment and downregulated P-gp expression levels compared with those in the negative control group. Additionally, silencing of OPNc impaired cell proliferative and colony formation abilities, as well as reversed the expression levels of EMT markers and EMT-related cytokines compared with those in the negative control cells. Notably, although stable OPNc overexpression resulted in increased A2780 cell proliferation, it notably increased CDDP sensitivity compared with that in the cells transfected with a control vector. These results suggested that OPNc silencing may represent a putative approach to sensitize resistant ovarian cancer cells to chemotherapeutic agents.