Mabuchi Miyuki, Tsujikawa Kazutake, Tanaka Akito
Department of Pharmacy, Laboratory of Chemical Biology, Advanced Medicinal Research Center, Hyogo Medical University, Kobe.
Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Anticancer Drugs. 2025 Jan 1;36(1):19-27. doi: 10.1097/CAD.0000000000001656. Epub 2024 Aug 26.
Prostate cancer antigen-1/ALKBH3, a DNA/RNA demethylase of 3-methylcytosine, 1-methyladenine (1-meA), and 6-meA, was found in prostate cancer as an important prognostic factor. Additionally, 1-meA has been associated with other cancers. The ALKBH3 inhibitor HUHS015 was found to be effective against prostate cancer both in vitro and in vivo . Herein, we investigated the effect of HUHS015 in combination with drugs for prostate cancer approved in Japan (including bicalutamide, cisplatin, mitoxantrone, prednisolone, ifosfamide, tegafur/uracil, docetaxel, dacarbazine, and estramustine) by treating DU145 cells with around IC 50 value concentrations of these drugs for 3 days. Additionally, the cells were observed for additional 9 days after drug removal. Combination treatment with dacarbazine, estramustine, tegafur/uracil, and HUHS015 showed a slight additive effect after 3 days. After drug washout of them and mitoxantrone, the combined effects and levels were enhanced and sustained, although the effects of each treatment alone declined. HUHS015 combined with cisplatin or docetaxel elicited synergistic and sustained effects. In vivo , combining HUHS015 and docetaxel, the first chemotherapeutic agent for castration-resistant prostate cancer, showed notable effects in the DU145 xenograft model. In conclusion, HUHS015 exhibited a synergistic effect with docetaxel and drugs acting on DNA in vitro , even after drug removal. Since cancer chemotherapy is typically administered during rest periods due to its high toxicity, combining it with an ALKBH3 inhibitor could be a promising strategy for enhancing cancer treatment, as it can elicit an additive effect during treatment, allowing dosage reduction, and synergistically sustain the effect after drug washout during rest periods.
前列腺癌抗原-1/ALKBH3是一种可作用于3-甲基胞嘧啶、1-甲基腺嘌呤（1-meA）和6-甲基腺嘌呤的DNA/RNA去甲基化酶，在前列腺癌中被发现是一个重要的预后因素。此外，1-meA还与其他癌症有关。已发现ALKBH3抑制剂HUHS015在体外和体内对前列腺癌均有效。在此，我们通过用这些药物的约IC50值浓度处理DU145细胞3天，研究了HUHS015与日本批准的前列腺癌药物（包括比卡鲁胺、顺铂、米托蒽醌、泼尼松龙、异环磷酰胺、替加氟/尿嘧啶、多西他赛、达卡巴嗪和雌莫司汀）联合使用的效果。此外，在去除药物后，对细胞再观察9天。达卡巴嗪、雌莫司汀、替加氟/尿嘧啶与HUHS015联合治疗3天后显示出轻微的相加效应。在将它们和米托蒽醌的药物洗脱后，联合效应和水平增强并持续，尽管每种单独治疗的效果有所下降。HUHS015与顺铂或多西他赛联合使用可产生协同和持续的效果。在体内，将HUHS015与去势抵抗性前列腺癌的第一种化疗药物多西他赛联合使用，在DU145异种移植模型中显示出显著效果。总之，HUHS015在体外与多西他赛以及作用于DNA的药物表现出协同效应，即使在药物去除后也是如此。由于癌症化疗因其高毒性通常在休息期给药，将其与ALKBH3抑制剂联合使用可能是增强癌症治疗的一种有前景的策略，因为它在治疗期间可产生相加效应，允许减少剂量，并在休息期药物洗脱后协同维持效果。
