JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia

• Published in: Biomedicine & pharmacotherapy Vol. 144; p. 112330
• Main Authors: Aranda-Tavío, Haidée, Recio, Carlota, Martín-Acosta, Pedro, Guerra-Rodríguez, Miguel, Brito-Casillas, Yeray, Blanco, Rosa, Junco, Vanessa, León, Javier, Montero, Juan Carlos, Gandullo-Sánchez, Lucía, McNaughton-Smith, Grant, Zapata, Juan Manuel, Pandiella, Atanasio, Amesty, Angel, Estévez-Braun, Ana, Fernández-Pérez, Leandro, Guerra, Borja
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.12.2021; Elsevier
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; BCR-ABL1; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chronic myelogenous leukemia; Drug Resistance, Neoplasm; Drug Synergism; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - genetics; Fusion Proteins, bcr-abl - metabolism; Gene Expression Regulation, Neoplastic; Humans; Imatinib Mesylate - pharmacology; Imatinib resistance; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Naphthoquinones - pharmacology; Protein Kinase Inhibitors - pharmacology; Signal Transduction; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Synergism; Chronic myelogenous leukemia; Imatinib resistance; Synergism; BCR-ABL1
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.112330

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. [Display omitted] •Naphthoquinone-pyrone antitumor activity against chronic myelogenous leukemia.•BCR-ABL1 protein levels downregulation by a rapid posttranslational mechanism.•Synergism with Imatinib inhibiting cell proliferation and STAT5 activation.•Overcoming resistance to Imatinib generated by different mechanisms.