Novel dihydrochalcone from Fissistigma latifolium targets STAT3 and survivin to overcome multidrug resistance cancers in vitro and in vivo

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy Pub Date : 2025-05-05 DOI:10.1016/j.biopha.2025.118125

I-Ting Wu , Ying-Tzu Chang , Ching-Hui Su , Yu-Hsuan Lan , Chin-Chuan Hung

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引用次数: 0

Abstract

Background

Multidrug resistance (MDR) remains a significant challenge in cancer chemotherapy, with no FDA-approved drugs currently available for its treatment. Natural chalcones, known for their diverse bioactivities, have emerged as potential therapeutic candidates.

Purpose

This study aimed to investigate the potential of 4,6-dimethoxy-2,5-quinodihydrochalcone (DODHC), a compound derived from Fissistigma latifolium, in overcoming MDR in cancer and to elucidate its underlying molecular mechanisms.

Methods

The reversal effects of DODHC on MDR were evaluated using cytotoxicity assays. The molecular mechanisms were explored through apoptosis- and cell cycle-related assays, STAT3 ELISA, western blotting, docking simulations, and a zebrafish model. The impact of DODHC on P-glycoprotein (P-gp) activity was assessed using the Calcein-AM uptake assay.

Results

DODHC promoted apoptosis in MDR cancer cells by suppressing survivin expression and activating the extrinsic apoptotic pathway. It also induced G2/M phase cell cycle arrest by downregulating cell division control protein 2 (CDC2) and cyclin B1 (CCNB1), thereby inhibiting cell proliferation. Additionally, DODHC reduced both total and phosphorylated STAT3 levels in MDR cancer cells without affecting P-gp activity. In vivo, DODHC significantly inhibited tumor growth in MDR cancer models, both as a monotherapy and in combination with paclitaxel.

Conclusion

This study highlights DODHC as a dual inhibitor of STAT3 and survivin, demonstrating its potential as a promising candidate for the treatment of MDR cancers.

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新型二氢查尔酮在体内外靶向STAT3和survivin以克服多药耐药癌症

背景：多药耐药（MDR）仍然是癌症化疗中的一个重大挑战，目前没有fda批准的药物可用于治疗。天然查尔酮以其多样的生物活性而闻名，已成为潜在的治疗候选者。目的研究从裂茎中提取的化合物4,6-二甲氧基-2,5-喹诺二氢查尔酮（DODHC）在抗癌耐多药治疗中的作用，并探讨其潜在的分子机制。方法采用细胞毒法评价DODHC对MDR的逆转作用。通过细胞凋亡和细胞周期相关实验、STAT3 ELISA、western blotting、对接模拟和斑马鱼模型来探索其分子机制。DODHC对p -糖蛋白（P-gp）活性的影响采用钙素- am摄取法进行评估。结果dodhc通过抑制survivin表达和激活外源性凋亡通路促进MDR癌细胞凋亡。通过下调细胞分裂控制蛋白2 （CDC2）和细胞周期蛋白B1 （CCNB1）诱导G2/M期细胞周期阻滞，从而抑制细胞增殖。此外，DODHC降低了耐多药癌细胞中总STAT3和磷酸化STAT3水平，而不影响P-gp活性。在体内，DODHC无论是单独治疗还是与紫杉醇联合治疗，都能显著抑制耐多药癌症模型中的肿瘤生长。结论本研究强调了DODHC作为STAT3和survivin的双重抑制剂，显示了其作为治疗耐多药癌症的有希望的候选物的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biomedicine & Pharmacotherapy 医学-药学

CiteScore

11.90

自引率

2.70%

发文量

1621

审稿时长

48 days

期刊介绍： Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.