pevonedistat and Kidney-Neoplasms

Renal medullary carcinoma (RMC) is a highly aggressive cancer in need of new therapeutic strategies. The neddylation pathway can protect cells from DNA damage induced by the platinum-based chemotherapy used in RMC. We investigated if neddylation inhibition with pevonedistat will synergistically enhance antitumour effects of platinum-based chemotherapy in RMC.. We evaluated the IC. The RMC cell lines demonstrated IC. Our results suggest that pevonedistat synergises with carboplatin to inhibit RMC cell and tumour growth through inhibition of DNA damage repair. These findings support the development of a clinical trial combining pevonedistat with platinum-based chemotherapy for RMC.

Topics: Carboplatin; Carcinoma, Medullary; Carcinoma, Renal Cell; Humans; Kidney Neoplasms

MLN4924 is a second-generation inhibitor that targets ubiquitin-proteasome system by inhibiting neddylation activation enzyme (NAE), and subsequently blocking the neddylation-dependent activation of Cullin-RING E3 ligases (CRLs), which leads to the accumulation of CRLs substrates and hence, suppressing diverse tumor development. In this study, we investigated the potential application of this first-in-class inhibitor MLN4924 in the treatment of human renal cell carcinoma both in vitro and in vivo.. The impact of MLN4924 on renal cancer cells was determined by measuring viability (MTS), proliferation cell count test and clonogenic assays, cell cycle progression (flow cytometry with propidium iodide staining), apoptosis (flow cytometry with annexin V-FITC labeling) and DNA damage (immunofluorescent staining). The cell cycle regulatory molecules, apoptosis-related molecules, and cell stress-related proteins were examined by Western blotting. The influence of tumor cell migration was analyzed by wound healing assays. A well-established SCID xenograft mouse model was used to evaluate the effects of MLN4924 on tumor growth in vivo.. The data showed that MLN4924 induced a dose-dependent cytotoxicity, anti-proliferation, anti-migration, and apoptosis in human renal cancer cells; and caused cell cycle arrested at the G2 phase. In addition, the E2 conjugating enzymes of Neddylation UBE2M played a major role in the proliferation control of renal cancer cells. Finally, we confirmed MLN4924 inhibited tumor growth in a RCC xenograft mouse model with minimal general toxicity.. We concluded that MLN4924 induces apoptosis and cell cycle arrest. These findings implied that MLN4924 provides a novel strategy for the treatment of RCC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cellular Senescence; Cyclopentanes; DNA Damage; Dose-Response Relationship, Drug; Flow Cytometry; Humans; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Pyrimidines; Ubiquitin-Activating Enzymes; Ubiquitin-Conjugating Enzymes; Xenograft Model Antitumor Assays

Inhibition of protein neddylation pathway has emerged an attractive anticancer strategy in preclinical studies by using Nedd8-activating enzyme (NAE) inhibitor MLN4924 (Pevonedistat). Previous studies have reported the antitumor activity of MLN4924 mediated by its efficacy on apoptosis, autophagy and senescence. However, whether MLN4924 has any effect on renal carcinoma cells (RCC) remains unexplored. Here we reported that MLN4924 specifically inhibited protein neddylation pathway, leading to statistically significantly suppress the proliferation, survival and migration of RCC cells by inducing G

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; Cell Survival; Cyclopentanes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Kidney Neoplasms; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Structure-Activity Relationship; Tumor Cells, Cultured; Up-Regulation

Neddylation is a post-translational protein modification associated with cancer development. MLN4924 is a neddylation inhibitor currently under investigation in multiple phase I studies on various malignancies, and its clincal name is Pevonedistat. It has been documented that MLN4924 blocks Cullins neddylation and inactivates CRLs and, in turn, triggers cell-cycle arrest, apoptosis, senescence and autophagy in many cancer cells. In this study, we investigated the anti-tumor effect of MLN4924 in human clear cell renal carcinoma (ccRCC). Levels of both Nedd8 activating enzyme E1 and Nedd8-conjugating enzyme E2 were higher in ccRCC tissues and RCC cancer cells than in normal. Moreover, MLN4924 treatment led to rapid inhibition of Cullin1 neddylation and notably suppressed growth and survival as well as migration in a dose-and time-dependent manner. Mechanistic studies revealed that MLN4924 induced the accumulation of a number of CRL substrates, including p21, p27 and Wee1 to trigger DNA damage and induce growth arrest at the G2/M phase. MLN4924 also induced anti-migration and anti-invasion by activating E-cadherin and repressing Vimentin. Taken together, this study provides the first evidence that neddylation pathway is overactive in ccRCC and that MLN4924 induces dose-dependent anti-proliferation, anti-migration, anti-invasion in ccRCC cells. The study thus indicates that MLN4924 has potential therapeutic value for the clinical treatment of renal cancer.

Topics: Apoptosis; Autophagy; Carcinoma, Renal Cell; Cell Cycle Checkpoints; Cell Movement; Cell Proliferation; Cyclopentanes; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms; NEDD8 Protein; Protein Processing, Post-Translational; Proteolysis; Pyrimidines; Tumor Cells, Cultured; Ubiquitins