PDF(Pubmed)
Abstract：
PV-10 is a 10% formulation of rose bengal sodium that has potent immunotherapeutic and anti-cancer activity against various tumors, including metastatic melanoma and refractory neuroblastoma. Currently, PV-10 is undergoing clinical testing for refractory metastatic neuroendocrine cancer and melanomas. However, preclinical investigation of PV-10 activity and its mechanisms against phenotypically and molecularly diverse adult solid tumors had not been conducted. In a panel of human cell lines derived from breast, colorectal, head and neck, and testicular cancers, we demonstrated that PV-10 induces cytotoxicity by apoptotic and autophagic pathways involving caspase-mediated PARP cleavage, downregulation of SQSTM1/p62, and upregulation of beclin-1. Treatment with PV-10 also consistently reduced phosphorylation of WNK1, which has been implicated in cancer cell migration and autophagy inhibition. By wound healing assay, PV-10 treatment inhibited the migration of cancer cells. Finally, significant inhibition of tumor growth was also noted in tumor-bearing mice treated with PV-10 by intralesional or systemic administration. In addition to known PV-10-mediated tumor-specific cytotoxic effects, we identified the mechanisms of PV-10 and provide new insights into its effect on autophagy and metastasis. Our data provide essential mechanism-based evidence and biomarkers of activity to formulate clinical studies of PV-10 in the future.
摘要：
PV-10是玫瑰孟加拉钠的10％制剂，对各种肿瘤具有有效的免疫治疗和抗癌活性，包括转移性黑色素瘤和难治性神经母细胞瘤。目前,PV-10正在进行难治性转移性神经内分泌癌和黑色素瘤的临床试验。然而,尚未进行PV-10活性及其针对表型和分子多样性成人实体瘤的机制的临床前研究。在一组来源于乳腺的人类细胞系中，结直肠,头部和颈部,和睾丸癌，我们证明PV-10通过涉及caspase介导的PARP裂解的凋亡和自噬途径诱导细胞毒性，SQSTM1/p62下调，Beclin-1上调。用PV-10处理也一致地减少WNK1的磷酸化,这与癌细胞迁移和自噬抑制有关。通过伤口愈合试验，PV-10处理抑制了癌细胞的迁移。最后,通过病灶内或全身给药,在用PV-10治疗的荷瘤小鼠中也注意到肿瘤生长的显著抑制.除了已知的PV-10介导的肿瘤特异性细胞毒性作用，我们确定了PV-10的机制,并为其对自噬和转移的影响提供了新的见解.我们的数据为将来制定PV-10的临床研究提供了必要的基于机制的证据和活性生物标志物。
