Mortalin, a member of the Hsp70 family of proteins, is commonly enriched in many types of cancers. It promotes carcinogenesis and metastasis in multiple ways of which the inactivation of the tumor suppressor activity of p53 has been firmly established. The downregulation of mortalin and/or disruption of mortalin–p53 interactions by small molecules has earlier been shown to activate p53 function yielding growth arrest/apoptosis in cancer cells. Mortaparibs (Mortaparib, MortaparibPlus, and MortaparibMild) are chemical inhibitors of mortalin isolated by cell-based two-way screening involving (i) a shift in the mortalin staining pattern from perinuclear (characteristics of cancer cells) to pancytoplasmic (characteristics of normal cells) and (ii) the nuclear enrichment of p53. They have similar structures and also cause the inhibition of PARP1 and hence were named Mortaparibs. In the present study, we report the anticancer and anti-metastasis activity of MortaparibMild(4-[(4-amino-5-thiophen-2-yl-1,2,4-triazol-3-yl)sulfanylmethyl]-N-(4-methoxyphenyl)-1,3-thiazol-2-amine) in p53-null cells. By extensive molecular analyses of cell proliferation, growth arrest, and apoptosis pathways, we demonstrate that although it causes relatively weaker cytotoxicity compared to Mortaparib and MortaparibPlus, its lower concentrations were equally potent to inhibit cell migration. We developed combinations (called MortaparibMix-AP, MortaparibMix-AM, and MortaparibMix-AS) consisting of different ratios of three Mortaparibs for specifically enhancing their anti-proliferation, anti-migration, and antistress activities, respectively. Based on the molecular analyses of control and treated cells, we suggest that the three Mortaparibs and their mixtures may be considered for further laboratory and clinical studies validating their use for the treatment of cancer as well as prevention of its relapse and metastasis.
Mortalin是Hsp70蛋白家族成员，在多种癌症中普遍高表达。它通过多种方式促进癌变与转移，其中对p53肿瘤抑制活性的抑制作用已得到明确证实。既往研究表明，通过小分子下调mortalin表达或破坏mortalin-p53相互作用可激活p53功能，导致癌细胞生长停滞/凋亡。Mortaparibs（包括Mortaparib、MortaparibPlus和MortaparibMild）是通过细胞双向筛选分离出的mortalin化学抑制剂，筛选标准包括：（1）mortalin染色模式从核周型（癌细胞特征）向全细胞质型（正常细胞特征）转变；（2）p53在细胞核内富集。这些化合物结构相似，同时具有PARP1抑制作用，故命名为Mortaparib系列。本研究报道了MortaparibMild（4-[(4-氨基-5-噻吩-2-基-1,2,4-三唑-3-基)硫代甲基]-N-(4-甲氧基苯基)-1,3-噻唑-2-胺）在p53缺失细胞中的抗癌及抗转移活性。通过对细胞增殖、生长停滞和凋亡通路的系统分子分析，我们发现虽然其细胞毒性较Mortaparib和MortaparibPlus相对较弱，但较低浓度下仍能同等有效地抑制细胞迁移。我们开发了三种Mortaparib化合物不同比例的组合物（分别命名为MortaparibMix-AP、MortaparibMix-AM和MortaparibMix-AS），可特异性增强其抗增殖、抗迁移及抗应激活性。基于对对照组和处理组细胞的分子分析，我们认为这三种Mortaparib化合物及其组合物值得进一步开展实验室与临床研究，以验证其在癌症治疗及预防复发转移方面的应用价值。
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