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Objectives: Pancreatic cancer (PC) is a very lethal malignancy with a scarcity of treatment options. Although erlotinib- and gemcitabine-based treatments have been approved for PC, their effectiveness is limited. The present study is aimed at exploring the molecular and epigenetic mechanisms of anticancer activities of homoharringtonine (HHT) and its interaction with erlotinib to develop a potential therapeutic strategy for PC. Methods: The RT-qPCR, western blotting, immunofluorescence and expression-vectors and oligonucleotide transfection were employed to determine the expression characteristics of onco-factors. Anticancer activities were determined by MTT, colony forming, and flowcytometric analysis. Dual luciferase assay was conducted to confirm putative target of miR-130b-3p. In-vivo experiments were followed by immunohistochemical assay. Key findings: The EphB4/JAK2/STAT3 pathway drives the growth and proliferation of PC through induction of prosurvival factors and cell cycle mediators. HHT directly and epigenetically via miR-130b-3p targets EphB4, leading to downregulation of JAK2/STAT3 pathway. The inactivation of STAT3 results in diminution of antiapoptotic factors and cell cycle mediators. HHT also enhances the anticancer activity of erlotinib. Conclusions: HHT demonstrates potential anticancer activities in PC by downregulating EphB4/JAK2/STAT3 signalling. HHT also produces synergistic effects with erlotinib. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is a highly devastating neoplasm due to its irrepressible characteristics and propensity to override the available treatment strategies. Rapid prevalence and enormous severity of this cancer urgently demand the exploration of novel approaches for the development of effective therapeutic measures. Metabolic derangement is one of the hallmarks of cancers which restructures mitochondrial activities and biological pathways. Apart from their bioenergetic and biosynthetic functions, mitochondria are also implicated in a myriad of cellular functions including proliferation, differentiation, apoptosis, senescence, homeostasis, and other cell regulatory mechanisms. It has been noted that PC, like other types of cancers, exploits these activities in favor of tumor growth and survival by inducing mitochondrial dysfunctions such as mitochondrial-DNA mutation, metabolic enzyme modification, ROS generation, mitophagy, evasion of apoptosis, and mitochondrial biogenesis. During pancreatic carcinogenesis, a large number of onco-factors including Bcl-2 family proteins, NF-κB, HIFs, NRF2, NOX, MFNs, DRP1, DUSP6, Cyp-D, PARKIN, and others are dysregulated, resulting into reprogramming of metabolic pathways and cellular kinetics. Hence, targeted interventions in these metabolic derangements may present some effective anticancer approaches. The current review gives an insight into various mitochondrial disorders and their targetable molecules in PC which may provide certain novel opportunities in the pursuit of therapeutic development. Furthermore, we have also discussed certain treatment perspectives in PC based on specific mitochondrial activities. • Mitochondrial derangements can switch the metabolic phenotype to impart numerous tumorigenic features. • Mitochondrial derangements reinforce the oncogenic mechanisms of development, progression, and chemoresistance in pancreatic cancer. • The metabolic alterations present plausible mitochondrial targets and therapeutic opportunities. • The natural agents and small bioactive compounds are promising anticancer effects based on mitochondrial targets. [ABSTRACT FROM AUTHOR]

[Display omitted] Pancreatic Cancer (PC) is a severe form of malignancy all over the world. Delayed diagnosis and chemoresistance are the major factors contributing to its poor prognosis and high mortality rate. The genetic and epigenetic regulations of biological pathways further complicate the progression and chemotherapy response to this cancer. MicroRNAs (MiRNAs) involvement has been observed in all types of cancers including PC. The understanding and categorization of miRNAs according to their specific targets are very important to develop early diagnostic and therapeutic interventions. The current review, emphasizing recent research findings, has categorized miRNAs that directly target the potential onco-factors that act as central converging signal-nodes in five major cancer-related pathways i.e., MAPK/ERK, JAK/STAT, Wnt/β-catenin, AKT/mTOR, and TGFβ in PC. The therapeutic perspectives of miRNAs in PC have also been discussed. This will help to understand the interplay of various miRNAs within foremost signaling pathways and develop a multifactorial approach to treat difficult-to-treat PC. [ABSTRACT FROM AUTHOR]