Yue Lili, Huang Zhi-Ming, Fong Stephen, Leong Stanley, Jakowatz James G, Charruyer-Reinwald Alex, Wei Maria, Ghadially Ruby
Departments of aDermatology bSurgery, University California at San Francisco cDepartment of Dermatology, Veterans Affairs Medical Center, San Francisco dDepartment of Surgery, University California at Irvine, Irvine, California, USA.
Melanoma Res. 2015 Apr;25(2):138-48. doi: 10.1097/CMR.0000000000000144.
Cells with aldehyde dehydrogenase activity (ALDH+) are the most tumorigenic cells in many cancers, including melanoma, making ALDH a candidate therapeutic target. We examined the effects of chemical inhibition of ALDH1 on the response of human melanoma xenografts to chemotherapy and the effects of ALDH1A1 RNA silencing on melanoma growth and metastasis. Addition of ALDH1 inhibitors (e.g. diethylaminobenzaldehyde) to dacarbazine chemotherapy, not only reduced tumor growth in vivo, but also resulted in a significant decrease in the number of residual cells capable of tumorigenesis. shRNA depletion of ALDH1A1 in melanoma cells resulted not only in a significant delay in appearance of xenograft melanomas and reduction in growth, but also significantly decreased the number of metastases and metastatic burden after lateral tail vein injections in mice. In summary, ALDH1 inhibition in combinatorial therapy with dacarbazine reduced the number of residual tumorigenic cells post-therapy and ALDH1A1 depletion had marked inhibitory effects on both melanoma growth and metastasis. These findings suggest that ALDH1 inhibition may not only be able to provide a therapeutic advantage in melanoma treatment, but may also prevent rapid relapse after therapy, as residual tumorigenic cells are fewer and metastatic ability is diminished.
具有乙醛脱氢酶活性的细胞（ALDH+）是包括黑色素瘤在内的许多癌症中最具致瘤性的细胞，这使得ALDH成为一个潜在的治疗靶点。我们研究了化学抑制ALDH1对人黑色素瘤异种移植瘤化疗反应的影响，以及ALDH1A1基因沉默对黑色素瘤生长和转移的影响。在达卡巴嗪化疗中添加ALDH1抑制剂（如二乙氨基苯甲醛），不仅能在体内抑制肿瘤生长，还能使具有致瘤能力的残留细胞数量显著减少。黑色素瘤细胞中ALDH1A1的短发夹RNA（shRNA）缺失，不仅显著延迟了异种移植黑色素瘤的出现并降低了其生长速度，还显著减少了小鼠经尾静脉注射后的转移灶数量和转移负担。总之，在与达卡巴嗪的联合治疗中抑制ALDH1可减少治疗后残留的致瘤细胞数量，而缺失ALDH1A1对黑色素瘤的生长和转移均有显著抑制作用。这些发现表明，抑制ALDH1不仅可能在黑色素瘤治疗中提供治疗优势，还可能防止治疗后快速复发，因为残留的致瘤细胞减少且转移能力减弱。
