RNAi Screen Identifies AXL Inhibition Combined with Cannabinoid WIN55212-2 as a Potential Strategy for Cancer Treatment

• Published in: Pharmaceuticals (Basel, Switzerland) Switzerland), 2024-11, Vol.17 (11), p.1465
• Main Authors: Li, Feifei, Gong, Hang, Jia, Xinfei, Gao, Chang, Jia, Peng, Zhao, Xin, Chen, Wenxia, Wang, Lili, Xue, Nina
• Format: Article
• Language: English
• Subjects: Apoptosis; AXL; cancer; Cancer therapies; Cannabidiol; cannabinoid; Care and treatment; Cell cycle; Cell growth; Colon cancer; combination chemotherapy; cytotoxic T cells; Development and progression; Diagnosis; Drug dosages; Drug therapy, Combination; Health aspects; Kinases; Medical prognosis; Metastasis; Patient outcomes; Proteins; Psychotropic drugs; RNAi screening; Tumors
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph17111465

: Cannabinoids are commonly used as adjuvant cancer drugs to overcome numerous adverse side effects for patients. The aim of this study was to identify the target genes that show a synergistic anti-tumor role in combination with the cannabinoid WIN55212-2 in vitro and in vivo. : A human kinome RNAi library was used to screen the targeted gene that silencing plus WIN55212-2 treatment synergistically inhibited cancer cell growth in an INCELL Analyzer 2000. Cell viability, cell phase arrest and apoptosis were evaluated by MTT and flow cytometry assay. In vivo combined anti-tumor effects and regulatory mechanisms were detected in immunocompromised and immunocompetent mice. : Using RNAi screening, we identified the tyrosine receptor kinase AXL as a potential gene whose silencing plus WIN55212-2 treatment synergistically inhibited the proliferation of cancer cells in an INCELL Analyzer 2000. Subsequently, we demonstrated that inhibition of AXL by TP-0903 potentiated the inhibitory role of WIN55212-2 on cellular viability, colony formation and 3D tumor sphere in HCT-8 cells. Meanwhile, TP-0903 plus WIN55212-2 treatment promoted the apoptosis of HCT-8 cells. We then investigated the synergistic anti-tumor effect of TP-0903 and WIN55212-2 using colon cancer cell xenografts in immunocompromised and immunocompetent mice. The in vivo study demonstrated that combined administration of TP-0903 plus WIN55212-2 effectively reduced tumor volume and microvessel density and promoted apoptotic cells of tumor tissues in HCT-8 exogenous mice compared to either TP-0903 or WIN55212-2 treatment alone. Moreover, in addition to tumor suppression, the combination therapy of TP-0903 and WIN55212-2 induced the infiltration of cytotoxic CD8 T cells and significantly reduced mTOR and STAT3 activation in tumor tissues of C57BL/6J mice bearing MC-38 cells. : This study demonstrated that targeting AXL could sensitize cannabinoids to cancer therapy by interfering with tumor cells and tumor-infiltrating CD8 T cells.