Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India.
Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India.
Int J Biol Macromol. 2023 Jul 1;242(Pt 1):124749. doi: 10.1016/j.ijbiomac.2023.124749. Epub 2023 May 7.
Cyclophosphamide (CP) is one of the most widely used anticancer drugs for various malignancies. However, its long-term use leads to ALDH1A1-mediated inactivation and subsequent resistance which necessitates the development of potential ALDH1A1 inhibitors. Currently, ALDH1A1 inhibitors from different chemical classes have been reported, but these failed to reach the market due to safety and efficacy problems. Developing a new treatment from the ground requires a huge amount of time, effort, and money, therefore it is worthwhile to improve CP efficacy by proposing better adjuvants as ALDH1A1 inhibitors. Herein, the database constituting the FDA-approved drugs with well-established safety and toxicity profiles was screened through already reported machine learning models by our research group. This model is validated for discriminating the ALDH1A1 inhibitors and non-inhibitors. Virtual screening protocol (VS) from this model identified four FDA-approved drugs, raloxifene, bazedoxifene, avanafil, and betrixaban as selective ALDH1A1 inhibitors. The molecular docking, dynamics, and water swap analysis also suggested these drugs to be promising ALDH1A1 inhibitors which were further validated for their CP resistance reversal potential by in-vitro analysis. The in-vitro enzymatic assay results indicated that raloxifene and bazedoxifene selectively inhibited the ALDH1A1 enzyme with IC values of 2.35 and 4.41 μM respectively, whereas IC values of both the drugs against ALDH2 and ALDH3A1 was >100 μM. Additional in-vitro studies with well-reported ALDH1A1 overexpressing A549 and MIA paCa-2 cell lines suggested that mafosfamide sensitivity was further ameliorated by the combination of both raloxifene and bazedoxifene. Collectively, in-silico and in-vitro studies indicate raloxifene and bazedoxifene act as promising adjuvants with CP that may improve the quality of treatment for cancer patients with minimal toxicities.
环磷酰胺 (CP) 是用于各种恶性肿瘤的最广泛使用的抗癌药物之一。然而，其长期使用导致 ALDH1A1 介导的失活和随后的耐药性，这需要开发潜在的 ALDH1A1 抑制剂。目前，已经报道了来自不同化学类别的 ALDH1A1 抑制剂，但由于安全性和疗效问题，这些药物未能进入市场。从头开始开发一种新的治疗方法需要大量的时间、精力和资金，因此，通过提出更好的 ALDH1A1 抑制剂作为辅助药物来提高 CP 的疗效是值得的。在此，通过我们研究小组已经报道的机器学习模型筛选构成 FDA 批准药物的数据库，这些药物具有良好的安全性和毒性概况。该模型经过验证可用于区分 ALDH1A1 抑制剂和非抑制剂。该模型的虚拟筛选 (VS) 协议确定了四种 FDA 批准的药物，雷洛昔芬、巴多昔芬、阿伐那非和贝曲沙班为选择性 ALDH1A1 抑制剂。分子对接、动力学和水交换分析也表明这些药物具有成为有前途的 ALDH1A1 抑制剂的潜力，并通过体外分析进一步验证了它们逆转 CP 耐药的潜力。体外酶测定结果表明，雷洛昔芬和巴多昔芬分别选择性地抑制 ALDH1A1 酶，IC 值分别为 2.35 和 4.41 μM，而两种药物对 ALDH2 和 ALDH3A1 的 IC 值均>100 μM。在具有良好报道的 ALDH1A1 过表达 A549 和 MIA paCa-2 细胞系中的进一步体外研究表明，雷洛昔芬和巴多昔芬的组合进一步改善了 mafosfamide 的敏感性。总之，体内外研究表明，雷洛昔芬和巴多昔芬作为 CP 的有前途的辅助药物，可能会提高癌症患者的治疗质量，同时最大限度地减少毒性。
