A Novel Thienopyrimidine Analog, TPH104, Mediates Immunogenic Cell Death in Triple-Negative Breast Cancer Cells.
A Novel Thienopyrimidine Analog, TPH104, Mediates Immunogenic Cell Death in Triple-Negative Breast Cancer Cells.
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DOI：
10.3390/cancers13081954
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发表时间：
2021-04-18
期刊：
影响因子：
5.2
通讯作者：
Tiwari AK
中科院分区：
文献类型：
--
作者：
Tukaramrao DB;Malla S;Saraiya S;Hanely RA;Ray A;Kumari S;Raman D;Tiwari AK
三阴性乳腺癌（TNBC）是最致命和最具侵袭性的乳腺癌亚型，其缺乏雌激素受体、孕酮受体和人表皮生长因子受体2（HER 2），使得其不适合基于激素或HER 2的治疗。与非TNBC相比，TNBC以其较高的复发率，较差的预后和较高的转移率而闻名，因为尽管患者最初对通过称为细胞凋亡的程序性细胞死亡形式杀死癌细胞的化疗有反应，但他们后来发展出耐药性并停止对治疗作出反应，占所有乳腺癌死亡的四分之一。在这项研究中，我们报告了一种新的化合物，TPH 104，它在TNBC细胞中引起独特的非凋亡性细胞死亡。在用TPH 104治疗后，TNBC细胞膨胀并破裂，释放免疫原性标记物，这些标记物警告并激活免疫系统以进一步识别和攻击邻近的乳腺癌细胞。已经提出增强肿瘤免疫原性微环境以规避三阴性乳腺癌（TNBC）抗性并增加常规化疗的功效。在这里，我们报告了一种新的化疗化合物，TPH 104，它诱导TNBC细胞系MDA-MB-231中的免疫原性细胞死亡，通过增加树突状细胞（DC）的刺激能力，IC 50值为140 nM。与溶剂孵育的细胞相比，TPH 104（5 µM）显著增加了MDA-MB-231细胞上清液中的ATP水平，并将细胞内钙网蛋白动员至质膜。用TPH 104（1-5 μM）孵育MDA-MB-231细胞12 h可显著增加TNF-α mRNA水平。死亡MDAMB-231细胞培养上清与TPH 104共同孵育可促进小鼠骨髓来源DC的成熟、MHC-II和CD 86的表达以及TNF-α、IL-6和IL-12的mRNA表达。总之，这些结果表明，TPH 104部分地通过激活DC诱导TNBC细胞中的免疫原性细胞死亡。
Triple-negative breast cancer (TNBC) is the most lethal and aggressive subtype of breast cancer that lacks an estrogen receptor, the progesterone receptor and the human epidermal growth factor receptor 2 (HER2), making it unsuitable for hormonal- or HER2-based therapy. TNBC is known for its higher relapse rate, poorer prognosis and higher rate of metastasis compared to non-TNBC because although patients initially respond to chemotherapy that kills cancer cells through a form of programmed cell death called apoptosis, they later develop chemoresistance and stop responding to the treatment, accounting for one fourth of all breast cancer deaths. In this study, we report a novel compound, TPH104, that elicits a unique, non-apoptotic cell death in TNBC cells. Upon treatment with TPH104, TNBC cells swell and burst, releasing immunogenic markers that alert and activate the immune system to further recognize and attack the neighboring breast cancer cells. Enhancing the tumor immunogenic microenvironment has been suggested to circumvent triple-negative breast cancer (TNBC) resistance and increase the efficacy of conventional chemotherapy. Here, we report a novel chemotherapeutic compound, TPH104, which induces immunogenic cell death in the TNBC cell line MDA-MB-231, by increasing the stimulatory capacity of dendritic cells (DCs), with an IC50 value of 140 nM. TPH104 (5 µM) significantly increased ATP levels in the supernatant and mobilized intracellular calreticulin to the plasma membrane in MDA-MB-231 cells, compared to cells incubated with the vehicle. Incubating MDA-MB-231 cells for 12 h with TPH104 (1–5 µM) significantly increased TNF-α mRNA levels. The supernatants of dying MDAMB-231 cells incubated with TPH104 increased mouse bone marrow-derived DC maturation, the expression of MHC-II and CD86 and the mRNA expression of TNF-α, IL-6 and IL-12. Overall, these results indicate that TPH104 induces immunogenic cell death in TNBC cells, in part, by activating DCs.
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影响因子：
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