Therapeutic potential of the phosphino Cu(I) complex (HydroCuP) in the treatment of solid tumors
Therapeutic potential of the phosphino Cu(I) complex (HydroCuP) in the treatment of solid tumors
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DOI：
10.1038/s41598-017-13698-1
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发表时间：
2017-10-24
影响因子：
4.6
通讯作者：
Marzano, Cristina
中科院分区：
文献类型：
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作者：
Gandin, Valentina;Ceresa, Cecilia;Marzano, Cristina
[Cu(THP)(4)][PF6](AhCuP)是一种在生理介质中高度溶解和稳定的膦铜(I)配合物，已被开发为一种可能替代铂类药物用于抗癌治疗的药物。氢氧化铜通过诱导内质网应激抑制实体瘤细胞的生长，从而导致细胞死亡，对肿瘤细胞比对非肿瘤细胞有更好的抗肿瘤作用。本研究的目的是通过触发未折叠蛋白反应(UPR)通路，在体内、同基因和异种移植的小鼠实体瘤模型中评价氢化铜磷的治疗潜力。在铂类药物方面，氢氧化铜诱导的肿瘤生长减少量显著高于铂类药物，动物毒性最小。在人结直肠癌异种移植瘤中，在奥沙利铂敏感和耐药模型中，氢化铜磷化疗都是非常有效的。良好的体内耐受性也与令人鼓舞的生物分布有关。此外，没有观察到药物相关的神经毒性和肾毒性的迹象。总之，这些结果表明，值得进一步研究，以评估其对广泛的实体恶性肿瘤的治疗活性。
[Cu(thp)(4)][PF6] (HydroCuP) is a phosphino copper(I) complex highly soluble and stable in physiological media that has been developed as a possible viable alternative to platinum-based drugs for anticancer therapy. HydroCuP potently inhibited the growth of human cancer cells derived from solid tumors by inducing endoplasmatic reticulum (ER) stress thus leading to cell death through paraptosis with a preferential efficacy against cancer rather than non-cancer cells. Aim of the present study was to assess the therapeutic potential of HydroCuP in vivo, in syngenic and xenograft murine models of solid tumors by triggering the Unfolded Protein Response (UPR) pathway. With respect to platinum drugs, HydroCuP induced a markedly higher reduction of tumor growth associated with minimal animal toxicity. In human colorectal cancer xenografts, chemotherapy with HydroCuP was extremely effective in both oxaliplatin-sensitive and resistant models. The favorable in vivo tolerability of HydroCuP was also correlated to an encouraging biodistribution profile. Additionally, no signs of drug-related neurotoxicity and nephrotoxicity were observed. Altogether, these results demonstrate that HydroCuP appears worth of further investigation to evaluate its therapeutic activity towards a broad spectrum of solid malignancies.