Department of Chemistry, NAmur MEdicine & Drug Innovation Center (NAMEDIC-NARILIS), University of Namur, 61 rue de Bruxelles, B-5000 Namur, Belgium.
URBC - NARILIS, University of Namur, 61 rue de Bruxelles, Namur, Belgium.
Biochem Pharmacol. 2019 Apr;162:224-236. doi: 10.1016/j.bcp.2019.01.004. Epub 2019 Jan 7.
Hypoxia is one of the most important biological phenomena that influences cancer agressiveness and chemotherapy resistance. Cancer cells display dysregulated pathways notably resulting from oncogene expression. Tumors also show modifications in extracellular pH, extracellular matrix remodeling, neo-angiogenesis, hypoxia compared to normal tissues. Classically, the conventional anticancer therapies are efficient in cancer cells in normoxic conditions but under hypoxia, chemoresistance may occur. The addition of compounds that potentiate their activity in low oxygen environment could be a strategy to counteract this resistance. To identify new compounds active in hypoxia, we screened one hundred molecules with different chemical structures from an internal chemolibrary. Their potential ability to increase the activity of taxol and etoposide independently of their mechanism of action has been assayed. After a first step of selection, based on biological/pharmacological properties and chemical structure analysis, we identified three potential hits. Two hits are closely related amides/ureas and the third is a thiosemicarbazone. The compounds present no activity in cancer and normal cells when used alone but demonstrate chemosensitizing activity under hypoxia. Finally, by analyzing cell death, the indole thiosemicarbazone was shown to be able to significantly potentiate apoptosis induced by taxol and etoposide in two models of cancer cell lines. This new compound could lead to the development of an original series of chemosensitizers active under hypoxia.
缺氧是影响癌症侵袭性和化疗耐药性的最重要的生物学现象之一。癌细胞表现出失调的途径，特别是由于癌基因表达。与正常组织相比，肿瘤还表现出细胞外 pH 值、细胞外基质重塑、新生血管形成、缺氧的改变。经典地，常规的抗癌疗法在常氧条件下对癌细胞有效，但在缺氧下，可能会发生化学耐药性。添加能够增强其在低氧环境中活性的化合物可能是对抗这种耐药性的一种策略。为了鉴定在缺氧条件下具有活性的新化合物，我们从内部化学文库中筛选了一百种具有不同化学结构的分子。独立于其作用机制，测定了它们增加紫杉醇和依托泊苷活性的潜在能力。在基于生物学/药理学特性和化学结构分析的初步筛选后，我们确定了三个有潜力的靶点。两个靶点是密切相关的酰胺/脲，第三个是硫代卡巴腙。这些化合物单独使用时在癌细胞和正常细胞中均无活性，但在缺氧下表现出化学增敏活性。最后，通过分析细胞死亡，发现吲哚硫代卡巴腙能够显著增强紫杉醇和依托泊苷在两种癌细胞系模型中诱导的细胞凋亡。这种新化合物可能会导致开发出一系列在缺氧下具有活性的新型化学增敏剂。
