Akonnor Abraham, Makise Masaki, Kuniyasu Akihiko
Laboratory of Molecular Cell Pharmacology, Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan.
ACS Omega. 2023 Jun 26;8(27):24467-24476. doi: 10.1021/acsomega.3c02415. eCollection 2023 Jul 11.
Triple-negative breast cancer is an aggressive subtype with a high recurrence rate, potential for metastasis, and a poor prognosis. The chemokine receptor, CXCR4, is a promising molecular target in breast cancer therapy. Here, we have developed a CXCR4-targeted antitumor peptidomimetic (named CTCE-KLAK), which is a fusion of the CXCR4 receptor antagonist CTCE-9908 and the D-form of proapoptotic peptide (KLAKLAK), for the treatment of breast cancer. First, we investigated the antitumor activity of CTCE-KLAK against various breast cancer cells and noncancerous mammary epithelial cells. CTCE-KLAK showed cell-selective cytotoxicity and induced rapid necrotic cell death in breast cancer cells but not in normal cells. In contrast, unconjugated peptides such as the carboxylate analogues of CTCE-9908 and (KLAKLAK) were not cytotoxic to these cells. The tumor selectivity of CTCE-KLAK for cytotoxic activity depends on its internalization into tumor cells. There was no cleavage of caspase-3, caspase-7, or PARP1 in CTCE-KLAK-treated cells. In addition, cell death by CTCE-KLAK was not prevented by z-VAD-fmk, a pan-caspase inhibitor that inhibits cisplatin-induced cell death. These data indicate that the CTCE-KLAK conjugate is a cell-selective inducer of necrosis. Furthermore, we evaluated the antitumor activity of CTCE-KLAK in the 4T1 mouse metastatic breast cancer model. Intravenous administration of CTCE-KLAK significantly inhibited tumor growth and lung metastasis. Together, these findings suggest that the necrosis-inducing peptidomimetic CTCE-KLAK is a promising CXCR4-targeted agent for treating triple-negative breast cancer.
三阴性乳腺癌是一种侵袭性亚型，具有高复发率、转移潜能和不良预后。趋化因子受体CXCR4是乳腺癌治疗中一个有前景的分子靶点。在此，我们开发了一种靶向CXCR4的抗肿瘤拟肽（命名为CTCE-KLAK），它是CXCR4受体拮抗剂CTCE-9908与促凋亡肽的D型（KLAKLAK）的融合体，用于治疗乳腺癌。首先，我们研究了CTCE-KLAK对各种乳腺癌细胞和非癌性乳腺上皮细胞的抗肿瘤活性。CTCE-KLAK表现出细胞选择性细胞毒性，并在乳腺癌细胞中诱导快速坏死性细胞死亡，但在正常细胞中则不会。相比之下，未偶联的肽，如CTCE-9908和（KLAKLAK）的羧酸盐类似物，对这些细胞没有细胞毒性。CTCE-KLAK细胞毒性活性的肿瘤选择性取决于其内化进入肿瘤细胞。在CTCE-KLAK处理的细胞中，caspase-3、caspase-7或PARP1没有裂解。此外，z-VAD-fmk（一种抑制顺铂诱导细胞死亡的泛半胱天冬酶抑制剂）不能阻止CTCE-KLAK引起的细胞死亡。这些数据表明CTCE-KLAK偶联物是坏死的细胞选择性诱导剂。此外，我们在4T1小鼠转移性乳腺癌模型中评估了CTCE-KLAK的抗肿瘤活性。静脉注射CTCE-KLAK显著抑制肿瘤生长和肺转移。总之，这些发现表明，诱导坏死的拟肽CTCE-KLAK是一种有前景的靶向CXCR4的治疗三阴性乳腺癌的药物。
