Targeting Liver Cancer and Associated Pathologies in Mice with a Mitochondrial VDAC1-Based Peptide

Hepatocellular carcinoma (HCC) is the third most lethal cancer worldwide. Despite progress in identifying risk factors, the incidence of HCC is increasing. Moreover, therapeutic options are limited and survival is poor. Therefore, alternative and innovative therapeutic strategies are urgently required. R-Tf-D-LP4, a cell-penetrating peptide derived from the mitochondrial multifunctional protein the voltage-dependent anion channel (VDAC1), is identified here as a highly effective liver cancer treatment. Recently, we demonstrated that R-Tf-D-LP4 induced apoptosis and inhibited tumor growth in mouse models. We now demonstrate that R-Tf-D-LP4 induced apoptosis in cancer liver-derived cell lines and inhibited tumor growth in three different liver cancer mouse models. These included diethylnitrosamine (DEN)-induced HCC, metabolically high-fat diet–induced HCC, and using a subcutaneous HepG2 cell xenograft model. Intravenous injection of the peptide into tumor-carrying DEN-treated mice resulted in dose-dependent inhibition of tumor growth up to complete tumor elimination. TUNEL staining of liver sections demonstrated peptide-induced apoptosis. Hematoxylin/eosin and Sirius red staining of liver sections showed decreased fibrotic formation. Immunohistochemical staining demonstrated reduced numbers of α-SMA–expressing cells in R-Tf-D-LP4–treated mouse livers. Additionally, macrophage presence in liver tissue was reduced in R-Tf-D-LP4–treated mice. Liver sections from DEN-treated mice showed steatohepatic pathology, reflected as fatty liver, inflammation, ballooning degeneration, and fibrosis; all were eliminated upon peptide treatment. Peptide treatment also inhibited tumor development in a nonalcoholic steatohepatitis–hepatocellular carcinoma mouse model induced by HFD. In HepG2 subcutaneous tumor xenografts, R-Tf-D-LP4 inhibited tumor growth. Conclusion: These results show that the VDAC1-based peptide R-Tf-D-LP4 has multiple effects on liver cancer cells, leading to impairment of cell energy and metabolism homeostasis, induction of apoptosis, and elimination of liver cancer-associated processes, and thus represents a promising therapeutic approach for liver cancer

The Prelude on Novel Receptor and Ligand Targets Involved in the Treatment of Diabetes Mellitus

Metabolic disorders are a group of disorders, due to the disruption of the normal metabolic process at a cellular level. Diabetes Mellitus and Tyrosinaemia are the majorly reported metabolic disorders. Among them, Diabetes Mellitus is a one of the leading metabolic syndrome, affecting 5 to 7 % of the population worldwide and mainly characterised by elevated levels of glucose and is associated with two types of physiological event disturbances such as impaired insulin secretion and insulin resistance. Up to now, various treatment strategies are like insulin, alphaglucosidase inhibitors, biguanides, incretins were being followed. Concurrently, various novel therapeutic strategies are required to advance the therapy of Diabetes mellitus. For the last few decades, there has been an extensive research in understanding the metabolic pathways involved in Diabetes Mellitus at the cellular level and having the profound knowledge on cell-growth, cell-cycle, and apoptosis at a molecular level provides new targets for the treatment of Diabetes Mellitus. Receptor signalling has been involved in these mechanisms, to translate the information coming from outside. To understand the various receptors involved in these pathways, we must have a sound knowledge on receptors and ligands involved in it. This review mainly summarises the receptors and ligands which are involved the Diabetes Mellitus. Finally, researchers have to develop the alternative chemical moieties that retain their affinity to receptors and efficacy. Diabetes Mellitus being a metabolic disorder due to the glucose surfeit, demands the need for regular exercise along with dietary changes

Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology

Abstract Background Alzheimer's disease (AD) exhibits mitochondrial dysfunctions associated with dysregulated metabolism, brain inflammation, synaptic loss, and neuronal cell death. As a key protein serving as the mitochondrial gatekeeper, the voltage-dependent anion channel-1 (VDAC1) that controls metabolism and Ca2+ homeostasis is positioned at a convergence point for various cell survival and death signals. Here, we targeted VDAC1 with VBIT-4, a newly developed inhibitor of VDAC1 that prevents its pro-apoptotic activity, and mitochondria dysfunction. Methods To address the multiple pathways involved in AD, neuronal cultures and a 5 × FAD mouse model of AD were treated with VBIT-4. We addressed multiple topics related to the disease and its molecular mechanisms using immunoblotting, immunofluorescence, q-RT-PCR, 3-D structural analysis and several behavioral tests. Results In neuronal cultures, amyloid-beta (Aβ)-induced VDAC1 and p53 overexpression and apoptotic cell death were prevented by VBIT-4. Using an AD-like 5 × FAD mouse model, we showed that VDAC1 was overexpressed in neurons surrounding Aβ plaques, but not in astrocytes and microglia, and this was associated with neuronal cell death. VBIT-4 prevented the associated pathophysiological changes including neuronal cell death, neuroinflammation, and neuro-metabolic dysfunctions. VBIT-4 also switched astrocytes and microglia from being pro-inflammatory/neurotoxic to neuroprotective phenotype. Moreover, VBIT-4 prevented cognitive decline in the 5 × FAD mice as evaluated using several behavioral assessments of cognitive function. Interestingly, VBIT-4 protected against AD pathology, with no significant change in phosphorylated Tau and only a slight decrease in Aβ-plaque load. Conclusions The study suggests that mitochondrial dysfunction with its gatekeeper VDAC1 is a promising target for AD therapeutic intervention, and VBIT-4 is a promising drug candidate for AD treatment