The current clinical interventions in malignant melanomas are met with poor response to therapy due to dynamic regulation of multiple melanoma signaling pathways consequent to administration of single target agents. In this context of limited response to single target agents, novel candidate molecules capable of effectively inducing tumor inhibition along with targeting multiple critical nodes of melanoma signaling assume translational significance. In this regard, we investigated the anti-cancer effects of a novel dichlorophenyl urea compound called COH-SR4 in melanoma. The SR4 treatment decreased the survival and inhibited the clonogenic potential of melanomas along with inducing apoptosis in vitro cultures. SR4 treatments lead to inhibition of GST activity along with causing G2/M phase cell cycle arrest. Oral administration of 4 mg/kg SR4 leads to effective inhibition of tumor burdens in both syngeneic and nude mouse models of melanoma. The SR4 treatment was well tolerated and no overt toxicity was observed. The histopathological examination of resected tumor sections revealed decreased blood vessels, decrease in the levels of angiogenesis marker, CD31, and proliferation marker, Ki67, along with an increase in pAMPK levels. Western blot analyses of resected tumor lysates revealed increased PARP cleavage, Bim, pAMPK along with decreased pAkt, vimentin, fibronectin, CDK4 and cyclin B1. Thus, SR4 represents a novel candidate for the further development of mono and combinatorial therapies to effectively target aggressive and therapeutically refractory melanomas.

中文翻译：

---

1,3-双（3,5-二氯苯基）脲化合物“COH-SR4”抑制黑色素瘤的增殖并激活细胞凋亡。

由于施用单一靶点药物后多种黑色素瘤信号通路的动态调节，目前对恶性黑色素瘤的临床干预对治疗反应不佳。在对单一靶点药物反应有限的背景下，能够有效诱导肿瘤抑制以及靶向黑色素瘤信号传导的多个关键节点的新型候选分子具有转化意义。在这方面，我们研究了一种名为 COH-SR4 的新型二氯苯基脲化合物在黑色素瘤中的抗癌作用。SR4 处理降低了黑色素瘤的存活率并抑制了黑色素瘤的克隆形成潜力，同时在体外培养物中诱导细胞凋亡。SR4 处理导致 GST 活性的抑制以及 G2/M 期细胞周期停滞。口服 4 mg/kg SR4 可有效抑制黑色素瘤同基因和裸鼠模型中的肿瘤负荷。SR4 治疗耐受性良好，未观察到明显毒性。切除肿瘤切片的组织病理学检查显示血管减少，血管生成标志物 CD31 和增殖标志物 Ki67 水平降低，同时 pAMPK 水平增加。切除的肿瘤裂解物的蛋白质印迹分析显示 PARP 裂解增加、Bim、pAMPK 以及 pAkt、波形蛋白、纤连蛋白、CDK4 和细胞周期蛋白 B1 减少。因此，SR4 代表了进一步开发单一和组合疗法以有效靶向侵袭性和治疗难治性黑色素瘤的新候选者。