Neumann-Mufweba Alexis, Kimani Serah, Khan Saif Feroz, Chibale Kelly, Prince Sharon
Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, 7925, Cape Town, South Africa.
Department of Chemistry, Faculty of Science, University of Cape Town, Rondebosch, 7701, Cape Town, South Africa.
EXCLI J. 2022 Apr 4;21:656-679. doi: 10.17179/excli2021-4323. eCollection 2022.
Breast cancer is the most common malignancy in women worldwide and it remains a global health burden, in part, due to poor response and tolerance to current therapeutics. Drug repurposing, which seeks to identify new indications for existing and investigational drugs, has become an exciting strategy to address these challenges. Here we describe the anti-breast cancer activity of a diaryl-imidazopyridazine compound, MMV652103, which was previously identified for its anti-plasmodial activity. We demonstrate that MMV652103 potently inhibits the oncogenic PI4KB and PIK3C2G lipid kinases, is selectively cytotoxic to MCF7 and T47D estrogen receptor positive breast cancer cells and inhibits their ability to survive and migrate. The underlying mechanisms involved included the induction of reactive oxygen species and activation of the DNA damage and p38 MAPK stress signaling pathways. This was associated with a G1 cell cycle arrest and an increase in levels of the cyclin-dependent kinase inhibitor p21 and activation of apoptotic and autophagic cell death pathways. Lastly, MMV652103 significantly reduced the weight and metastases of MCF7 induced tumors in an chick embryo model and displayed a favorable safety profile. These findings position MMV652103 as a promising chemotherapeutic in the treatment of oestrogen receptor positive breast cancers.
乳腺癌是全球女性中最常见的恶性肿瘤，它仍然是一项全球健康负担，部分原因是对当前疗法的反应不佳和耐受性差。药物重新利用旨在为现有和正在研究的药物确定新的适应症，已成为应对这些挑战的一项令人兴奋的策略。在此，我们描述了一种二芳基咪唑并哒嗪化合物MMV652103的抗乳腺癌活性，该化合物先前因其抗疟活性而被鉴定。我们证明，MMV652103能有效抑制致癌性PI4KB和PIK3C2G脂质激酶，对MCF7和T47D雌激素受体阳性乳腺癌细胞具有选择性细胞毒性，并抑制其存活和迁移能力。涉及的潜在机制包括活性氧的诱导以及DNA损伤和p38 MAPK应激信号通路的激活。这与G1期细胞周期停滞、细胞周期蛋白依赖性激酶抑制剂p21水平的增加以及凋亡和自噬性细胞死亡途径的激活有关。最后，在鸡胚模型中，MMV652103显著减轻了MCF7诱导肿瘤的重量和转移，并显示出良好的安全性。这些发现使MMV652103成为治疗雌激素受体阳性乳腺癌的一种有前景的化疗药物。
