Triad pyrazole-thiazole-coumarin heterocyclic core effectively inhibit HSP and drive cancer cells to apoptosis.

Intensive studies on hepatocellular carcinoma (HCC), which is spreading rapidly around the world and has a high mortality rate, is due to the lack of adequate preventive or curative treatment methods. Treating patients with HCC has become very challenging because of the heterogeneity in the patient population lead activation of different signaling pathways, and pathway crosstalk for patients. Therefore, understanding these molecular mechanisms and combining drugs with molecular therapies to overcome these drawbacks has become an area of utmost importance. In this study, the biological activities of the designed and characterized triad Pyrazole-Thiazol-Coumarin (PTC) compounds were determined by performing cell viability, qPCR array, apoptosis and cell cycle assays. One of the compounds (PTC10) implicitly suppresses multiple pathways (RAS/MAP kinase and PI3K-AKT) simultaneously. This action is provided by (i) arresting cancer cells at G2 phase, (ii) driving cancer cells to apoptosis and (iii) inhibiting HSP network. Remarkably, HSP is an apoptotic factor and help cancer cell to survive. HSP90 also coordinates with Cdk4/Cdc37, therefore inhibiting HSP both drives cells to arrest and apoptosis. ATP hydrolysis and aggregation assay further displayed specific HSP inhibition. Therefore, PTC provides a unique drug template for HCC treatment.

A Novel 6,8,9-Trisubstituted Purine Analogue Drives Breast Cancer Luminal A Subtype MCF-7 to Apoptosis and Senescence through Hsp70 Inhibition.

BACKGROUND: Cancer cells restrain apoptotic and senescence pathways through intracellular heat shock protein 70 (Hsp 70). These cells aid stimulus-independent growth, and their higher metabolism rate requires Hsps. Hsps compensate abnormally increased substrate protein folding rate of cancer cells. OBJECTIVE: Misfolding of substrate proteins especially signaling substrate proteins, may not function properly. Therefore, Hsp70 folds these substrate proteins into their native-fully functional states, and this mode of action helps cancer cell survival. METHODS: Targeting Hsps is promising cancer therapy, and in this study, 6,8,9-trisubstituted purine derivatives were designed and synthesized to inhibit Hsp70 and drive cancer cells to apoptosis. Further, oncogenic stimuli through inhibitors can induce an irreversible senescent state and senescence is a barrier to transformation. RESULTS: Hsp70 helps cancer cells to bypass the cellular senescence program, however, binding of N6-(4- isopropylaniline) analogue (7) depletes Hsp70 function as evidenced by aggregation assay and Hsp70 depletion induces senescence pathway. CONCLUSION: The purine-based inhibitor-compound 7 effectively inhibits MCF-7 cell line. Moreover, the therapeutic potential with regard to the senescence-associated secretory phenotype has complementary action. Dual action of the inhibitor not only drives the cells to apoptosis but also force the cells to be in the senescence state and provides promising results specially for luminal A type breast cancer therapy.