Abstract
Renal cell carcinoma has emerged as one of the leading causes of cancer-related deaths in the USA. Here, we examined the anticancer profile of oxindole derivatives (SH-859) in human renal cancer cells. Targeting 786-O cells by SH-859 inhibited cell growth and affected the protein kinase B/mechanistic target of rapamycin 1 pathway, which in turn downregulated the expression of glycolytic enzymes, including lactate dehydrogenase A and glucose transporter-1, as well as other signaling proteins. Treatment with SH-859 altered glycolysis, mitochondrial function, and levels of adenosine triphosphate and cellular metabolites. Flow cytometry revealed the induction of apoptosis and G0/G1 cell cycle arrest in renal cancer cells following SH-859 treatment. Induction of autophagy was also confirmed after SH-859 treatment by acridine orange and monodansylcadaverine staining, immunocytochemistry, and Western blot analyses. Finally, SH-859 also inhibited the tumor development in a xenograft model. Thus, SH-859 can serve as a potential molecule for the treatment of human renal carcinoma.
Highlights
Renal cell carcinoma (RCC) is categorized as the 6th and 10th most common cancer in males and females in the USA, respectively [1]
We studied how SH-859 inhibits the progression of clear cell renal cell carcinoma (ccRCC) tumorigenesis and the mechanism underlying its anticancer activity against the human kidney cancer cell line, 786-O
This suggests that the inhibition of PKM2 by SH-859 was dependent on its effect on glycolysis
Summary
Renal cell carcinoma (RCC) is categorized as the 6th and 10th most common cancer in males and females in the USA, respectively [1]. 65,340 new cases were diagnosed and 14,970 people died from RCC in the USA in 2018 [2], with it being considered the most hostile type [3,4]. The discovery and development of new therapeutic agents are necessary to overcome the resistance of cancer cells to chemotherapy and radiation therapy [7]. The development of targeted therapeutics against the mechanistic target of rapamycin 1 (mTOR) and tyrosine kinase (TK) has been a foremost breakthrough in anticancer drug discovery against ccRCC [7]. New therapeutic approaches have emerged as effective treatment possibilities against advanced ccRCC by inducing apoptosis and autophagy and targeting cancer cell metabolism [8]
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