Ivermectin Synergizes with Modulated Electro-hyperthermia and Improves Its Anticancer Effects in a Triple-Negative Breast Cancer Mouse Model

IF 4.9 Q1 CHEMISTRY, MEDICINAL ACS Pharmacology and Translational Science Pub Date : 2024-07-17 DOI:10.1021/acsptsci.4c0031410.1021/acsptsci.4c00314

Kenan Aloss, Pedro Henrique Leroy Viana, Syeda Mahak Zahra Bokhari, Nino Giunashvili, Csaba András Schvarcz, Dániel Bócsi, Zoltán Koós, Zoltán Benyó and Péter Hamar*,

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Abstract

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with limited treatment options. Modulated electro-hyperthermia (mEHT) is a novel adjuvant cancer therapy that induces selective cancer damage. However, mEHT upregulates heat shock protein beta 1 (HSPB1), a cancer-promoting stress chaperone molecule. Thus, we investigated whether ivermectin (IVM), an anthelmintic drug, may synergize with mEHT and enhance its anticancer effects by inhibiting HSPB1 phosphorylation. Isogenic 4T1 TNBC cells were inoculated into BALB/c mice and treated with mEHT, IVM, or a combination of both. IVM synergistically improved the tumor growth inhibition achieved by mEHT. Moreover, IVM downregulated mEHT-induced HSPB1 phosphorylation. Thus, the strongest cancer tissue damage was observed in the mEHT + IVM-treated tumors, coupled with the strongest apoptosis induction and proliferation inhibition. In addition, there was no significant body weight loss in mice treated with mEHT and IVM, indicating that this combination was well-tolerated. In conclusion, mEHT combined with IVM is a new, effective, and safe option for the treatment of TNBC.

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伊维菌素在三阴性乳腺癌小鼠模型中与调制电热疗法协同作用并提高其抗癌效果

三阴性乳腺癌（TNBC）是侵袭性最强的乳腺癌亚型，但治疗方法有限。调节性电高热（mEHT）是一种新型癌症辅助疗法，可诱导选择性癌症损伤。然而，mEHT 会上调热休克蛋白 beta 1（HSPB1），这是一种促癌应激伴侣分子。因此，我们研究了驱虫药伊维菌素（IVM）是否可与 mEHT 协同作用，通过抑制 HSPB1 磷酸化增强其抗癌效果。将同种异源的 4T1 TNBC 细胞接种到 BALB/c 小鼠体内，用 mEHT、IVM 或两者的组合进行治疗。IVM 协同改善了 mEHT 对肿瘤生长的抑制作用。此外，IVM 还能下调 mEHT 诱导的 HSPB1 磷酸化。因此，在经 mEHT + IVM 处理的肿瘤中观察到了最强烈的癌组织损伤，以及最强烈的凋亡诱导和增殖抑制。此外，接受 mEHT 和 IVM 治疗的小鼠体重没有明显下降，表明这种组合具有良好的耐受性。总之，mEHT 联合 IVM 是治疗 TNBC 的一种有效、安全的新选择。

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来源期刊

ACS Pharmacology and Translational Science Medicine-Pharmacology (medical)

CiteScore

10.00

自引率

3.30%

发文量

133

期刊介绍： ACS Pharmacology & Translational Science publishes high quality, innovative, and impactful research across the broad spectrum of biological sciences, covering basic and molecular sciences through to translational preclinical studies. Clinical studies that address novel mechanisms of action, and methodological papers that provide innovation, and advance translation, will also be considered. We give priority to studies that fully integrate basic pharmacological and/or biochemical findings into physiological processes that have translational potential in a broad range of biomedical disciplines. Therefore, studies that employ a complementary blend of in vitro and in vivo systems are of particular interest to the journal. Nonetheless, all innovative and impactful research that has an articulated translational relevance will be considered. ACS Pharmacology & Translational Science does not publish research on biological extracts that have unknown concentration or unknown chemical composition. Authors are encouraged to use the pre-submission inquiry mechanism to ensure relevance and appropriateness of research.