The Effect of HSF1 Activity Inhibitor of the Cardenolide Group (CL-43) on Tumor and Nontransformed Cells

Q4 Biochemistry, Genetics and Molecular Biology Cell and Tissue Biology Pub Date : 2024-08-06 DOI:10.1134/s1990519x24700354

S. A. Vladimirova, B. A. Margulis, I. V. Guzhova, A. D. Nicotina

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Abstract

The occurrence of intolerable side effects in patients undergoing chemotherapy continues to be a key clinical obstacle. In this regard, the search for tumor-specific therapy that does not have a toxic effect on healthy tissue remains an urgent task. It is known that heat-shock protein factor HSF1 is an important marker of cancer progression, and the products of its transcriptional activity allow tumor cells to successfully avoid the negative effects of antitumor therapy. Thereby, the use of drugs that inhibit HSF1 activity is a promising strategy. In this research, we found that the HSF1 activity inhibitor from the CL-43 cardenolide group exhibited a cytoprotective effect on primary nontransformed dermal fibroblast cells (DF-2) and made them less sensitive to etoposide, while in DLD1 tumor cells, on the contrary, we observed an increase in this sensitivity. In addition, we found that CL-43 affected the intranuclear transport of active HSF1, as well as increasing its activity and, accordingly, the synthesis of HSP70 in human fibroblasts, while CL-43 suppressed this activity in a dose-dependent manner in tumor cells. Our results indicate the high therapeutic potential of CL-43 and its uniqueness as a tumor-specific compound.

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卡地诺内酯类 HSF1 活性抑制剂（CL-43）对肿瘤细胞和非转化细胞的影响

摘要接受化疗的病人出现难以忍受的副作用仍然是临床上的一个主要障碍。因此，寻找对健康组织无毒副作用的肿瘤特异性疗法仍是一项紧迫任务。众所周知，热休克蛋白因子 HSF1 是癌症进展的重要标志，其转录活性的产物可使肿瘤细胞成功避免抗肿瘤治疗的负面影响。因此，使用抑制 HSF1 活性的药物是一种很有前景的策略。在这项研究中，我们发现 CL-43 Cardenolide 组的 HSF1 活性抑制剂对原代未转化的真皮成纤维细胞（DF-2）具有细胞保护作用，使其对依托泊苷的敏感性降低，而在 DLD1 肿瘤细胞中，我们观察到这种敏感性反而增加了。此外，我们还发现，CL-43 会影响活性 HSF1 的核内转运，提高其活性，从而增加人成纤维细胞中 HSP70 的合成，而在肿瘤细胞中，CL-43 会以剂量依赖的方式抑制 HSP70 的活性。我们的研究结果表明了 CL-43 的巨大治疗潜力及其作为肿瘤特异性化合物的独特性。

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来源期刊

Cell and Tissue Biology Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

0.80

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0.00%

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期刊介绍： The journal publishes papers on vast aspects of cell research, including morphology, biochemistry, biophysics, genetics, molecular biology, immunology. The journal accepts original experimental studies, theoretical articles suggesting novel principles and approaches, presentations of new hypotheses, reviews highlighting major developments in cell biology, discussions. The main objective of the journal is to provide a competent representation and integration of research made on cells (animal and plant cells, both in vivo and in cell culture) offering insight into the structure and functions of live cells as a whole. Characteristically, the journal publishes articles on biology of free-living and parasitic protists, which, unlike Metazoa, are eukaryotic organisms at the cellular level of organization.