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Photosensitizer DTP Co-Administered with Statins Potentiates Renal Carcinoma Therapy by Modulating Cholesterol to Enhance PDT.

ABSTRACT: Renal cell carcinoma (RCC) is the most common histological subtype of kidney cancer. Although targeted therapies and immune checkpoint inhibitors have markedly improved patient outcomes, their efficacy remains limited. In recent years, photodynamic therapy (PDT) has drawn increasing attention for its role in cancer treatment. To investigate the effects of the novel porphyrin-based photosensitizer meso-5-[ρ-DTPA-aminophenyl]-10,15,20 triphenylporphyrin (DTP) on RCC, we employed the human renal tubular epithelial cell line HK-2, human RCC cell lines 786-O, ACHN, and A498, as well as the murine renal carcinoma cell line Renca. We assessed intracellular DTP uptake, phototoxicity, and subcellular localization, and further explored potential mechanisms through next-generation sequencing. Our results showed that DTP uptake was significantly higher in RCC cells than in normal renal tubular epithelial cells, and DTP-PDT exerted pronounced phototoxic effects on RCC cells. Through sequencing and in vitro analyses, we found that DTP-PDT markedly reduced cholesterol levels in RCC cells while inducing compensatory upregulation of HMGCR. In vivo experiments further demonstrated that combining DTP-PDT with statins produced stronger anticancer effects. Overall, this study provides compelling evidence that DTP-PDT exhibits potent cytotoxic activity against renal cell carcinoma, and that statins can further enhance its therapeutic efficacy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328573 | GEO | 2026/04/23

REPOSITORIES: GEO

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Project description:The mechanism(s) for therapeutic resistance against c-Met/receptor tyrosine kinase (RTK) inhibitor(s) in renal cancer is totally unexplored. In renal cell carcinoma (RCC) cells, both AXL and c-Met are highly overexpressed and they form a complex. Interestingly, the prolonged treatment with c-Met/RTK inhibitor, Cabozantinib (Cabo), which is being used for the treatment of RCC patients, markedly increased the level of total c-Met and promoted renal cancer cell proliferation. This effect was confirmed not only in vitro but also in murine models and renal tumor tissues from Cabo-treated patients. Also, the lower concentrations of Cabo treatment could not inhibit HGF (c-Met ligand)-induced c-Met phosphorylation; rather they further increased the phosphorylation of the receptor and promoted downstream signaling events for tumor growth. In addition, our findings indicate that Cabo treatment induces AXL-c-Met association, and it interferes with the physiological degradation processes of c-Met within renal cancer cells. However, either the inhibition or the knockout of AXL could significantly overcome the therapeutic resistance against c-Met inhibitor(s); and it markedly induced apoptotic cell death through increased oxidative stress and inhibition of the transcription factor, Nrf2. We generated Cabo-resistant RCC cells, and we observed that the expression of both c-Met and AXL are markedly overexpressed in these cells; and the inhibition of AXL (through TP-0903) can resensitize the cancer cells to Cabo-mediated cell death. Moreover, we found significant differences in the epigenomic profile of the Cabo-resistant RCC cells compared with Cabo-sensitive cancer cells. Our in-depth studies suggest that AXL plays a major role in mediating therapeutic resistance against c-Met inhibitor(s). A combination therapy using c-Met inhibitor(s) in the presence of an AXL inhibitor can play a pivotal role to overcome acquired resistance against RTK inhibitors in renal cancer.

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Photosensitizer DTP Co-Administered with Statins Potentiates Renal Carcinoma Therapy by Modulating Cholesterol to Enhance PDT.

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