Sunitinib Combined with Th1 Cytokines Potentiates Apoptosis in Human Breast Cancer Cells and Suppresses Tumor Growth in a Murine Model of HER-2pos Breast Cancer.

IF 1.6 Q4 ONCOLOGY
International Journal of Breast Cancer Pub Date : 2021-04-14 eCollection Date: 2021-01-01 DOI:10.1155/2021/8818393
Nirmala Ghimirey, Chase Steele, Brian J Czerniecki, Gary K Koski, Loral E Showalter
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引用次数: 3

Abstract

Although immune-based therapies have made remarkable inroads in cancer treatment, they usually must be combined with standard treatment modalities, including cytotoxic drugs, to achieve maximal clinical benefits. As immunotherapies are further advanced and refined, considerable efforts will be required to identify combination therapies that will maximize clinical responses while simultaneously decreasing the unpleasant and sometimes life-threatening side effects of standard therapy. Over the last two decades, evidence has emerged that Th1 cytokines can play a central role in protective antitumor immunity and that combinations of Th1 cytokines can induce senescence and apoptosis in cancer cells. To explore the possibility of combining targeted drugs with Th1-polarizing vaccines, we undertook a study to examine the impact of combining Th1 cytokines with the relatively broad-spectrum receptor tyrosine kinase antagonist, sunitinib. We found that when a panel of five phenotypically diverse human breast cancer cell lines was subjected to treatment with sunitinib plus recombinant Th1 cytokines IFN-γ and TNF-α, synergistic effects were observed across a number of parameters including different aspects of apoptotic cell death. Interestingly, sunitinib was found to have a profoundly suppressive effect of T cell's capacity to secrete IFN-γ, indicating that in vivo use of this drug may hinder robust Th1 responses. Nonetheless, this suppression was circumvented in a mouse model of HER-2pos breast disease by supplying recombinant interferon-gamma to achieve a combination therapy significantly more potent than either agent.

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舒尼替尼联合Th1细胞因子增强人乳腺癌细胞凋亡并抑制HER-2pos乳腺癌小鼠模型的肿瘤生长
尽管免疫疗法在癌症治疗方面取得了显著进展,但它们通常必须与标准治疗方式(包括细胞毒性药物)联合使用,才能获得最大的临床效益。随着免疫疗法的进一步发展和完善,将需要付出相当大的努力来确定联合疗法,以最大限度地提高临床反应,同时减少标准疗法令人不快的、有时危及生命的副作用。在过去的二十年中,有证据表明Th1细胞因子可以在保护性抗肿瘤免疫中发挥核心作用,并且Th1细胞因子的组合可以诱导癌细胞衰老和凋亡。为了探索靶向药物与Th1极化疫苗联合使用的可能性,我们进行了一项研究,以检查Th1细胞因子与相对广谱受体酪氨酸激酶拮抗剂舒尼替尼联合使用的影响。我们发现,当一组五种表型不同的人类乳腺癌细胞系接受舒尼替尼加重组Th1细胞因子IFN-γ和TNF-α治疗时,在许多参数中观察到协同效应,包括凋亡细胞死亡的不同方面。有趣的是,舒尼替尼被发现对T细胞分泌IFN-γ的能力有深刻的抑制作用,这表明在体内使用这种药物可能会阻碍强大的Th1反应。然而,在HER-2pos乳腺疾病的小鼠模型中,通过提供重组干扰素- γ来实现比任何一种药物更有效的联合治疗,这种抑制被规避了。
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来源期刊
CiteScore
3.40
自引率
0.00%
发文量
25
审稿时长
19 weeks
期刊介绍: International Journal of Breast Cancer is a peer-reviewed, Open Access journal that provides a forum for scientists, clinicians, and health care professionals working in breast cancer research and management. The journal publishes original research articles, review articles, and clinical studies related to molecular pathology, genomics, genetic predisposition, screening and diagnosis, disease markers, drug sensitivity and resistance, as well as novel therapies, with a specific focus on molecular targeted agents and immune therapies.
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