PHP Biotech International Inc., Keller, TX 76248, USA.
Molecules. 2024 Apr 6;29(7):1646. doi: 10.3390/molecules29071646.
Breast cancer stands as the most prevalent type of tumor and a significant contributor to cancer-related deaths. Among its various subtypes, triple-negative breast cancer (TNBC) presents the worst prognosis due to its aggressive nature and the absence of effective treatments. Crotoxin, a protein found in the venom of genus snakes, has demonstrated notable antitumor activity against aggressive solid tumors. However, its application has been hindered by substantial toxicity in humans. In efforts to address this challenge, Crotoxin B-derived peptides were synthesized and evaluated in vitro for their antitumor potential, leading to the discovery of 3-NAntC. Treatment with 3-NAntC at 1 µg/mL for 72 h notably reduced the viability of MDA-MB-231 cells to 49.0 ± 17.5% ( < 0.0001), while exhibiting minimal impact on the viability of HMEC cells (98.2 ± 13.8%) under the same conditions. Notably, 3-NAntC displayed superior antitumoral activity in vitro compared to cisplatin and exhibited a similar effect to doxorubicin. Further investigation revealed that 3-NAntC decreased the proliferation of MDA-MB-231 cells and induced G2/M phase arrest. It primarily prompted optimal cell death by apoptosis, with a lower incidence of the less desirable cell death by necrosis in comparison to doxorubicin. Additionally, 3-NAntC demonstrated low LDH release, and its cytotoxicity remained unaffected by the autophagy inhibitor 3-MA. In an in vivo zebrafish model, 3-NAntC exhibited excellent tolerability, showing no lethal effects and a low rate of malformations at high doses of up to 75 mg/mL. Overall, 3-NAntC emerges as a novel synthetic peptide with promising antitumor effects in vitro against TNBC cells and low toxicity in vivo.
乳腺癌是最常见的肿瘤类型，也是癌症相关死亡的主要原因。在其各种亚型中，三阴性乳腺癌（TNBC）由于其侵袭性和缺乏有效治疗方法而预后最差。Crotoxin 是一种在蛇属蛇毒中发现的蛋白质，对侵袭性实体瘤具有显著的抗肿瘤活性。然而，其应用受到人体内大量毒性的阻碍。为了解决这一挑战，合成了 Crotoxin B 衍生肽并在体外评估其抗肿瘤潜力，从而发现了 3-NAntC。在相同条件下，用 3-NAntC 处理 1 µg/mL 72 h 可将 MDA-MB-231 细胞的活力显著降低至 49.0 ± 17.5%（<0.0001），而对 HMEC 细胞的活力影响最小（98.2 ± 13.8%）。值得注意的是，与顺铂相比，3-NAntC 在体外显示出优越的抗肿瘤活性，并且与阿霉素具有相似的作用。进一步的研究表明，3-NAntC 可降低 MDA-MB-231 细胞的增殖并诱导 G2/M 期阻滞。它主要通过凋亡诱导最佳细胞死亡，与阿霉素相比，坏死的发生率较低。此外，3-NAntC 显示出较低的 LDH 释放，其细胞毒性不受自噬抑制剂 3-MA 的影响。在体内斑马鱼模型中，3-NAntC 表现出良好的耐受性，在高达 75mg/mL 的高剂量下没有致死作用，畸形率也较低。总体而言，3-NAntC 是一种新型合成肽，具有体外对 TNBC 细胞的抗肿瘤作用和体内低毒性。
