Abstract
BackgroundGemcitabine is the standard first-line chemotherapy regimen for pancreatic cancer. However, its therapeutic value is substantially limited in pancreatic cancer patients due to occurrence of resistance towards gemcitabine. A strategy of combined chemo-regimens is widely employed in clinical settings in attempt to reduce the chance of developing therapeutic resistance. Valproic acid (VPA) has been reported as a promising anticancer drug in various clinical trials and studies. However, the clinical value and potential dose–effect of VPA in combination with gemcitabine for pancreatic cancer treatment are under investigated.ResultsIn this study, we determined the synergistic effect of VPA and gemcitabine and found that high-dose VPA significantly and dose-dependently enhanced the sensitivity of pancreatic cancer cells to gemcitabine. Intriguingly, low-dose VPA potentiated the migration and invasion of pancreatic cancer cells that already showed gemcitabine-induced motility. Moreover, low-dose VPA increased the reactive oxygen species (ROS) production, which activated AKT to further stimulate the activation of STAT3, Bmi1 expression and eventually promoted the migration and invasion of pancreatic cancer cells induced by gemcitabine. Whereas high-dose VPA stimulated excessive ROS accumulation that promoted p38 activation, which suppressed the activation of STAT3 and Bmi1.ConclusionPancreatic cancer cells respond differentially towards low- or high-dose of VPA in combination with gemcitabine, and a low VPA further potentiate pancreatic cancer cell to migrate and invade. Our results suggest that STAT3/Bmi1 signaling cascade, which is regulated by ROS-dependent, AKT- or p38-modulated pathways, primarily mediated the sensitivity and motility of pancreatic cancer cells towards combined gemcitabine and VPA regimen. These findings suggest a highly clinically relevant new mechanism of developing resistance against combined chemo-regimens, warranting further mechanistic and translational exploration for VPA in combination with gemcitabine and other chemotherapies.
Highlights
Gemcitabine is the standard first-line chemotherapy regimen for pancreatic cancer
The results indicated that Bmi1 contributed to the acquired migration and invasion induced by gemcitabine in combination with low-dose Valproic acid (VPA) treatment (Fig. 3b, c)
Our results suggest that signal transducers and activators of transcription 3 (STAT3) plays an important role in the acquired migration and invasion induced by gemcitabine and low-dose VPA cotreatment
Summary
Gemcitabine is the standard first-line chemotherapy regimen for pancreatic cancer. its therapeutic value is substantially limited in pancreatic cancer patients due to occurrence of resistance towards gemcitabine. The clinical value and potential dose–effect of VPA in combination with gemcitabine for pancreatic cancer treatment are under investigated. Intractable drug resistance is accepted as an important causation leading to a low efficacy of chemotherapy in pancreatic cancer [2,3,4]. Understanding the molecular mechanisms leading to chemoresistance and developing effective measures for sensitizing chemotherapy may be of great significance for pancreatic cancer. Recent progress has shown that gemcitabine combined with specific drugs can improve the overall survival of pancreatic cancer patients [7]. Developing combined therapeutics for exerting synergistic effects and reducing drug resistance may be promising strategies for combating pancreatic cancer [8,9,10]
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