Abstract:
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 Crotalus 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% (p < 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.
摘要:
乳腺癌是最常见的肿瘤类型,也是癌症相关死亡的重要原因。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而预后最差。毒素,在Crotalus属蛇的毒液中发现的一种蛋白质,已证明对侵袭性实体瘤具有显着的抗肿瘤活性。然而,它的应用受到对人类的巨大毒性的阻碍。为了应对这一挑战,合成了毒素B衍生的肽,并在体外评估了它们的抗肿瘤潜力,导致3-NAntC的发现。用3-NAntC以1µg/mL处理72小时显着降低MDA-MB-231细胞的活力至49.0±17.5%(p<0.0001),同时在相同条件下对HMEC细胞活力的影响最小(98.2±13.8%)。值得注意的是,与顺铂相比,3-NAntC在体外表现出优异的抗肿瘤活性,并且表现出与多柔比星相似的作用。进一步研究发现3-NAntC降低MDA-MB-231细胞的增殖并诱导G2/M期阻滞。它主要通过凋亡促使最佳细胞死亡,与多柔比星相比,坏死导致的细胞死亡发生率较低。此外,3-NAntC表现出低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表现出优异的耐受性,在高达75mg/mL的高剂量下,没有致死作用和畸形率低。总的来说,3-NAntC是一种新型合成肽,在体外对TNBC细胞具有良好的抗肿瘤作用,在体内具有低毒性。