Li Feifei, Gong Hang, Jia Xinfei, Gao Chang, Jia Peng, Zhao Xin, Chen Wenxia, Wang Lili, Xue Nina
Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100850, China.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Pharmaceuticals (Basel). 2024 Nov 1;17(11):1465. 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.
大麻素通常用作辅助抗癌药物，以克服患者的众多不良副作用。本研究的目的是鉴定在体外和体内与大麻素WIN55212-2联合发挥协同抗肿瘤作用的靶基因。
使用人类激酶组RNAi文库在INCELL Analyzer 2000中筛选沉默后与WIN55212-2处理协同抑制癌细胞生长的靶向基因。通过MTT和流式细胞术检测评估细胞活力、细胞周期阻滞和细胞凋亡。在免疫缺陷和免疫健全的小鼠中检测体内联合抗肿瘤作用和调节机制。
通过RNAi筛选，我们鉴定出酪氨酸受体激酶AXL是一个潜在基因，其沉默后与WIN55212-2处理在INCELL Analyzer 2000中协同抑制癌细胞增殖。随后，我们证明TP-0903抑制AXL增强了WIN55212-2对HCT-8细胞的细胞活力、集落形成和3D肿瘤球的抑制作用。同时，TP-0903加WIN55212-2处理促进了HCT-8细胞的凋亡。然后，我们在免疫缺陷和免疫健全的小鼠中使用结肠癌细胞异种移植研究了TP-0903和WIN55212-2的协同抗肿瘤作用。体内研究表明，与单独使用TP-0903或WIN55212-2处理相比，联合给予TP-0903加WIN55212-2可有效减小HCT-8移植瘤小鼠的肿瘤体积和微血管密度，并促进肿瘤组织中的凋亡细胞。此外，除了肿瘤抑制作用外，TP-0903和WIN55212-2的联合治疗还诱导了细胞毒性CD8 T细胞的浸润，并显著降低了携带MC-38细胞的C57BL/6J小鼠肿瘤组织中的mTOR和STAT3活化。
本研究表明，靶向AXL可通过干扰肿瘤细胞和肿瘤浸润性CD8 T细胞使大麻素对癌症治疗敏感。
