Non-coding RNAs are functional RNA molecules comprising the majority of human transcriptome. Only about 1.5% of the human genome is transcribed into messenger RNAs (mRNA) that are translated into proteins. Among the non-coding RNAs, miRNAs are extensively studied and miR targets in endothelial cells, perivascular cells, and angiogenic signaling are relatively well defined. MicroRNAs not only regulate transcripts in situ but also function as paracrine mediators in affecting angiogenesis at distant sites. Exosomal miRs are implicated in modulating endothelial cell function and angiogenesis. Thus miRs have been shown to affect tissue microenvironment in a multitude of ways. A comprehensive analysis of the role of miRs in modulation of angiogenesis and their impact on cardiovascular diseases is presented in this review.
Introduction Oxaliplatin is part of pancreatic cancer therapy in FOLFIRINOX or GEMOX/XELOX regimen. DNA damage repair is one of the factors responsible for oxaliplatin resistance that eventually develops in this cancer. Triptolide/Minnelide has been shown to be effective against pancreatic cancer in preclinical trials. In this study, we evaluated the efficacy of combination of triptolide and oxaliplatin against pancreatic cancer. Methods Highly aggressive pancreatic cancer cells (MIA PaCa-2 and PANC-1) were treated with oxaliplatin (0-10μM), low dose triptolide (50nM) or a combination of both for 24-48h. Cell viability, apoptosis and DNA damage was evaluated by appropriate methods. Nucleotide excision repair pathway components were quantitated using qPCR and western blot. Combination of low doses of Minnelide and oxaliplatin was tested in an orthotopic murine model of pancreatic cancer. Results Proliferation of pancreatic cancer cells was markedly inhibited by combination treatment. Triptolide potentiated apoptotic cell death induced by oxaliplatin and sensitized cancer cells towards oxaliplatin induced DNA damage by suppressing oxaliplatin induced DNA damage repair pathway. Combination of low doses of Minnelide and oxaliplatin inhibited tumor progression by inducing significant apoptotic cell death in these tumors. Conclusions Combination of low doses of Minnelide and oxaliplatin has immense potential to emerge as novel therapeutic strategy against pancreatic cancer.
Pancreatic cancer is estimated to be the 12th most common cancer in the United States in 2014 and yet this malignancy is the fourth leading cause of cancer-related death in the United States. Late detection and resistance to therapy are the major causes for its dismal prognosis. Apoptosis is an actively orchestrated cell death mechanism that serves to maintain tissue homoeostasis. Cancer develops from normal cells by accruing significant changes through one or more mechanisms, leading to DNA damage and mutations, which in a normal cell would induce this programmed cell death pathway. As a result, evasion of apoptosis is one of the hallmarks of cancer cells. PDAC is notoriously resistant to apoptosis, thereby explaining its aggressive nature and resistance to conventional treatment modalities. The current review is focus on understanding different intrinsic and extrinsic pathways in pancreatic cancer that may affect apoptosis in this disease.
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