Associate Laboratory i4HB, Department of Biological Sciences, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
UCIBIO-REQUIMTE, Department of Biological Sciences, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
Int J Mol Sci. 2022 Aug 31;23(17):9898. doi: 10.3390/ijms23179898.
Sunitinib and pazopanib are tyrosine kinase inhibitors (TKIs) used as first-line therapy for metastatic renal cell carcinoma (RCC). Although these TKIs are associated with similar survival outcomes, some differences have been reported in their safety profiles. In this work, traditional toxicological endpoints (cell viability and growth, oxidative stress, and nuclear morphology) and H NMR spectroscopy-based metabolomics analysis were used to provide new insights into the cytotoxicity and metabolic mechanisms underlying sunitinib and pazopanib treatments. Tumoral (Caki-1) and non-tumoral (HK-2) human renal cells were exposed to clinically relevant concentrations of sunitinib (2 µM) or pazopanib (50 µM). Sunitinib showed selectivity for cancer cells, inhibiting proliferation, and inducing apoptotic death of Caki-1 cells, whereas pazopanib had a similar cytotoxic effect in both tumoral and non-tumoral cells. H-NMR metabolomics unveiled a higher impact of sunitinib on the levels of intracellular metabolites of Caki-1 cells (seven dysregulated metabolites), suggesting dysregulations on amino acid, glutathione and glycerophospholipid metabolisms. In contrast, pazopanib had a higher impact on the levels of extracellular metabolites of Caki-1 cells (seven dysregulated metabolites in culture medium), unveiling alterations on amino acid and energetic metabolisms. In HK-2 cells, sunitinib caused only a minor increase in intracellular isoleucine levels, whereas pazopanib induced several alterations on the intracellular (three dysregulated metabolites) and extracellular (three dysregulated metabolites) compartments suggesting changes on amino acid, glycerophospholipid, and energy metabolisms. Our results demonstrate that these TKIs elicit distinct cellular and metabolic responses, with sunitinib showing better in vitro efficacy against target RCC cells and lesser nephrotoxic potential than pazopanib.
舒尼替尼和帕唑帕尼是用于治疗转移性肾细胞癌（RCC）的酪氨酸激酶抑制剂（TKI）。尽管这些 TKI 具有相似的生存结果，但在其安全性特征方面已有报道存在一些差异。在这项工作中，使用传统的毒理学终点（细胞活力和生长、氧化应激和核形态）和基于 H NMR 光谱的代谢组学分析，为舒尼替尼和帕唑帕尼治疗的细胞毒性和代谢机制提供了新的见解。将人肾肿瘤（Caki-1）和非肿瘤（HK-2）细胞暴露于临床相关浓度的舒尼替尼（2 μM）或帕唑帕尼（50 μM）。舒尼替尼对肿瘤细胞具有选择性，抑制增殖并诱导 Caki-1 细胞凋亡死亡，而帕唑帕尼对肿瘤和非肿瘤细胞均具有相似的细胞毒性作用。H-NMR 代谢组学揭示了舒尼替尼对 Caki-1 细胞细胞内代谢物水平的影响更大（七种失调代谢物），表明氨基酸、谷胱甘肽和甘油磷脂代谢紊乱。相比之下，帕唑帕尼对 Caki-1 细胞细胞外代谢物水平的影响更大（培养基中有七种失调代谢物），揭示了氨基酸和能量代谢的改变。在 HK-2 细胞中，舒尼替尼仅导致细胞内异亮氨酸水平略有增加，而帕唑帕尼诱导细胞内（三种失调代谢物）和细胞外（三种失调代谢物）发生几种变化，表明氨基酸、甘油磷脂和能量代谢发生变化。我们的结果表明，这些 TKI 引起不同的细胞和代谢反应，舒尼替尼对靶 RCC 细胞具有更好的体外疗效，且肾毒性潜力小于帕唑帕尼。
