CXCR4-Targeted Necrosis-Inducing Peptidomimetic for Treating Breast Cancer

Abstract

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)2, for the treatment of breast cancer. First, we investigated the in vitro 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 D(KLAKLAK)2 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 in vivo 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.

Nanoparticles for the Treatment of Bone Metastasis in Breast Cancer: Recent Advances and Challenges

“… 27 Moreover, high CXCR4 expression in BC is related to an increased occurrence of remote and bone metastases. 28 The CXCL12–CXCR4 axis induces cancer cells to release osteoclastogenic factors, enhancing bone metastasis. 29 Targeted therapies directed against this signaling axis may be clinically important for treating metastatic bone tumors.…”

Applications of self-assembled peptide hydrogels in anti-tumor therapy

“…43 Although CTCE-9980 demonstrated strong anti-metastatic effects in preclinical studies, its ability to inhibit tumor growth was limited. 57,58 To address this, Chen et al designed a peptide-drug conjugate (CTCE-DTX) that not only self-assembled into nanoparticles in aqueous environments but also targeted tumor cells with high expression of CXCR4. This design aimed to enhance the efficacy of docetaxel (DTX) while inhibiting bone metastasis in the case of triple-negative breast cancer.…”