Synergistic anticancer activity of HSP70 and HSF1 inhibitors in colorectal cancer cells: A new strategy for combination therapy.

Autor: Xu SM; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Liu XZ; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Wang L; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Huang WH; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Hu YT; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Chen SB; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Huang ZS; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: ceshzs@mail.sysu.edu.cn., Huang SL; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: lsshsl@mail.sysu.edu.cn.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2024 Dec 14; Vol. 1871 (3), pp. 167630. Date of Electronic Publication: 2024 Dec 14.
DOI: 10.1016/j.bbadis.2024.167630
Abstrakt: Background: The heat shock response (HSR) is a highly conserved mechanism that maintains intracellular homeostasis in response to various environmental and physiological stresses. Heat shock proteins (HSPs), particularly HSP70, play a pivotal role in this process as molecular chaperones. Although HSP70 inhibitors have demonstrated anti-cancer activity, their therapeutic potential has been limited by the negative feedback mechanism between HSP70 and heat shock factor 1 (HSF1). The combination of HSP70 inhibitors with HSF1 inhibitors has been proposed to overcome this limitation and enhance anti-cancer effects.
Methods: We combined HSP70 inhibitors (VER-155008 and YK-5) with an HSF1 inhibitor (DTHIB) in CRC cells and evaluated their effects on cell survival, apoptosis, and protein homeostasis.
Results: Strong synergistic effects were observed (combination index <0.5, ZIP score > 10) with the combination treatment, leading to decreased cell survival and increased apoptosis in CRC cells. Mechanistic studies revealed that HSP70 inhibitors activated the phosphorylation of HSF1, inducing HSP70 expression, and that the combination therapy resulted in more pronounced HSR inhibition and protein homeostasis disturbances.
Conclusion: The combination therapy of HSP 70 and HSF 1 inhibitors showed significant synergistic antitumor activity.
General Significance: Combining HSP70 and HSF1 inhibitors may be a promising anti-cancer strategy, offering a potential solution to overcome the negative feedback mechanism and enhance anti-cancer effects.
Competing Interests: Declaration of competing interest Zhi-Shu Huang reports financial support was provided by Sun Yat-Sen University. Shi-Liang Huang reports financial support was provided by Sun Yat-Sen University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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