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.
PV-10是一种浓度为10%的玫瑰红钠制剂，对多种肿瘤（包括转移性黑色素瘤和难治性神经母细胞瘤）具有强效免疫治疗和抗癌活性。目前，PV-10正在针对难治性转移性神经内分泌癌和黑色素瘤进行临床试验。然而，此前尚未对PV-10在表型和分子多样性成人实体瘤中的活性及其作用机制进行临床前研究。在一组源自乳腺癌、结直肠癌、头颈癌和睾丸癌的人类细胞系中，我们证实PV-10通过凋亡和自噬途径诱导细胞毒性，这些途径涉及caspase介导的PARP裂解、SQSTM1/p62的下调以及beclin-1的上调。PV-10处理还能持续降低WNK1的磷酸化水平，而WNK1与癌细胞迁移和自噬抑制有关。通过伤口愈合实验，PV-10处理抑制了癌细胞的迁移。最后，在荷瘤小鼠中，通过病灶内或全身给药PV-10也显著抑制了肿瘤生长。除了已知的PV-10介导的肿瘤特异性细胞毒性效应外，我们还确定了PV-10的作用机制，并为其对自噬和转移的影响提供了新的见解。我们的数据为未来制定PV-10的临床研究提供了基于机制的重要证据和活性生物标志物。
肿瘤(癌症)患者之家