MLN0905 effectively kills gemcitabine-resistant pancreatic cancer cells by targeting PLK1
Min Lin1, YongSha Pan1, Shanshan Han1
1Central Laboratory, Sanmen People's Hospital, No. 15 Taihe Road, Hairun Street, Sanmen, 317100, China.
Background:
Polo-like kinase 1 (PLK1) functionally mediates tumorigenesis of pancreatic cancer (PC) and associates with its drug resistance to gemcitabine, but related inhibitor therapies were poorly explored. MLN0905 is a novel small molecule inhibitor targeting PLK1. Here we investigate the therapeutic capacity for gemcitabine-resistant pancreatic cancer and related molecular mechanism of MLN0905.
Methods:
The inhibitory efficacy of MLN0905 on gemcitabine-resistant PC cell lines was assessed using cell viability assays, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), the colony formation assay, and flow cytometry detecting cell cycle or apoptosis. In addition, changes in the G2/M phase ratio were further analyzed. Cell cycle and apoptosis-related defects in MLN0905 treated PC cells were detected using western blot analysis. In addition, a subcutaneous tumor model of pancreatic cancer (PC) resistant to gemcitabine was established in vivo to investigate the inhibitory effect of MLN0905 in animal model and evaluate its safety to liver or kidney functions. Tumor volume, tumor weight, Ki67 expression, and the expression of cluster of differentiation 31 (CD31) were measured following the administration of MLN0905. Meanwhile, several detects for alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose (GLU) and creatinine (Cr) were also performed to further confirm the safety of MLN0905 in liver and kidney functions.
Results:
Experiments related to cell viability demonstrated that MLN0905 inhibited cell proliferation, induced cell cycle arrest, and promoted apoptosis in gemcitabine-resistant PC cell lines. Mechanistically, the phosphorylation level of PLK1 gradually deceased with the increase of drug concentration, while the expression of PHH3 and γH2A.x increased. In vivo evaluation showed the effective inhibition of MLN0905 in tumor growth and its good security.
Conclusions:
Our research has indicated that MLN0905 interferes with cancer cell DNA replication by specifically targeting PLK1, leading to cell cycle arrest and apoptosis, thereby preventing tumor growth and effectively eradicating gemcitabine-resistant pancreatic cancer cells, demonstrating satisfactory safety in this study. This research provides a detailed analysis of the interactions between MLN0905, PLK1, and gemcitabine resistance in the progression of pancreatic cancer, offering new prospects and insights for overcoming gemcitabine resistance in pancreatic cancer.
Insights
MLN0905, a novel Polo-like kinase 1 (PLK1) inhibitor, effectively eradicates gemcitabine-resistant pancreatic cancer by inducing cell cycle arrest and apoptosis. This study highlights MLN0905 as a promising therapeutic for overcoming drug resistance in pancreatic cancer.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Polo-like kinase 1 (PLK1) is implicated in pancreatic cancer (PC) tumorigenesis and gemcitabine resistance.
- Targeting PLK1 offers a potential therapeutic strategy for overcoming drug resistance in PC.
Purpose of the Study:
- To investigate the therapeutic efficacy of MLN0905, a novel PLK1 inhibitor, against gemcitabine-resistant pancreatic cancer.
- To elucidate the molecular mechanisms underlying MLN0905's action in pancreatic cancer.
Main Methods:
- In vitro assessment of MLN0905 efficacy using cell viability assays (MTT, colony formation) and flow cytometry in gemcitabine-resistant PC cell lines.
- Western blot analysis to detect cell cycle and apoptosis-related protein expression.
- In vivo evaluation in a subcutaneous xenograft model of gemcitabine-resistant PC to assess tumor growth inhibition and safety.
Main Results:
- MLN0905 inhibited proliferation, induced cell cycle arrest, and promoted apoptosis in gemcitabine-resistant PC cells.
- PLK1 phosphorylation decreased, while PHH3 and γH2A.x expression increased with MLN0905 treatment.
- In vivo studies demonstrated significant tumor growth inhibition and favorable safety profiles for MLN0905.
Conclusions:
- MLN0905 targets PLK1, interfering with DNA replication and leading to cell cycle arrest and apoptosis in pancreatic cancer.
- MLN0905 effectively overcomes gemcitabine resistance in pancreatic cancer, showing promising therapeutic potential.
- This study provides insights into overcoming gemcitabine resistance and suggests MLN0905 as a viable treatment option.
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