Abstract
Chronic myelogenous leukemia (CML) is a hematological malignancy that highly depends on the BCR-ABL1/STAT5 signaling pathway for cell survival. First-line treatments for CML consist of tyrosine kinase inhibitors that efficiently target BCR-ABL1 activity. However, drug resistance and intolerance are still therapeutic limitations in Ph+ cells. Therefore, the development of new anti-CML drugs that exhibit alternative mechanisms to overcome these limitations is a desirable goal. In this work, the antitumoral activity of JKST6, a naphthoquinone-pyrone hybrid, was assessed in imatinib-sensitive and imatinib-resistant human CML cells. Live-cell imaging analysis revealed JKST6 potent antiproliferative activity in 2D and 3D CML cultures. JKST6 provoked cell increase in the subG1 phase along with a reduction in the G0/G1 phase and altered the expression of key proteins involved in the control of mitosis and DNA damage. Rapid increases in Annexin V staining and activation/cleavage of caspases 8, 9 and 3 were observed after JKST6 treatment in CML cells. Of interest, JKST6 inhibited BCR-ABL1/STAT5 signaling through oncokinase downregulation that was preceded by rapid polyubiquitination. In addition, JKST6 caused a transient increase in JNK and AKT phosphorylation, whereas the phosphorylation of P38-MAPK and Src was reduced. Combinatory treatment unveiled synergistic effects between imatinib and JKST6. Notably, JKST6 maintained its antitumor efficacy in BCR-ABL1-T315I-positive cells and CML cells that overexpress BCR-ABL and even restored imatinib efficacy after a short exposure time. These findings, together with the observed low toxicity of JKST6, reveal a novel multikinase modulator that might overcome the limitations of BCR-ABL1 inhibitors in CML therapy.
Highlights
Chronic myelogenous leukemia (CML) is a hematopoietic stem cell disease associated with abnormal proliferation of clonal cells of the myelogenous lineage [1]
Interest ingly, JKST6 showed higher efficacy against cell lines derived from hematological malignancies (i.e., K562, MOLM-13, HL-60, HEL, MV 4.11, JURKAT cell lines) than against breast cancer-derived cells (i.e., BT-549, MDA-MB-231, HS-578 T) or nonmalignant cells (i.e., RAW 264.7, Vero, hMSCs, and peripheral blood mononuclear cells (PBMCs)) (Table 2)
Low concentrations (1 and 3 μM) of JKST6 showed no significant effect on PBMC viability compared to K562, whereas doxorubicin, a chemotherapeutic agent used in a broad spec trum of tumor types, reduced PBMC and K562 viability with similar potency (Fig. 1B)
Summary
Chronic myelogenous leukemia (CML) is a hematopoietic stem cell disease associated with abnormal proliferation of clonal cells of the myelogenous lineage [1]. Dysregulation of JAK/STAT signaling is a common factor in hematological can cers, in CML, where BCR-ABL1 can directly and indirectly activate STAT5, resulting in the overexpression of proto-oncogenic target genes (e.g., MYC and PIM1) [4,5]. It is not surprising that targeting BCR-ABL1 has marked a milestone in the treatment of CML
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