Novel antigens for targeted radioimmunotherapy in hepatocellular carcinoma.

Liver cancer is the sixth common cancer and forth cause of cancer-related death worldwide. Based on usually advanced stages of hepatocellular carcinoma (HCC) at the time of diagnosis, therapeutic options are limited and, in many cases, not effective, and typically result in the tumor recurrence with a poor prognosis. Radioimmunotherapy (RIT) offers a selective internal radiation therapy approach using beta or alpha emitting radionuclides conjugated with tumor-specific monoclonal antibodies (mAbs), or specific selective peptides. When compared to chemotherapy or radiotherapy, radiolabeled mAbs against cancer-associated antigens could provide a high therapeutic and exclusive radiation dose for cancerous cells while decreasing the exposure-induced side effects to healthy tissues. The recent advances in cancer immunotherapy, such as blockade of immune-checkpoint inhibitors (ICIs), has changed the landscape of cancer therapy, and the efficacy of different classes of immunotherapy has been tested in many clinical trials. Taking into account the use of ICIs in the liver tumor microenvironment, combined therapies with different approaches may enhance the outcome in the future clinical studies. With the development of novel immunotherapy treatment options in the recent years, there has been a great deal of information about combining the diverse treatment modalities to boost the effectiveness of immunomodulatory drugs. In this opinion review, we will discuss the recent advancements in RIT. The current status of immunotherapy and internal radiotherapy will be updated, and we will propose novel approaches for the combination of both techniques. Potential target antigens for radioimmunotherapy in Hepatocellular carcinoma (HCC). HCC radioimmunotherapy target antigens are the most specific and commonly accessible antigens on the surface of HCC cells. CTLA-4 ligand and receptor, TAMs, PD-1/PD-L, TIM-3, specific IEXs/TEXs, ROBO1, and cluster of differentiation antigens CD105, CD147 could all be used in HCC radioimmunotherapy. Abbreviations: TAMs, tumor-associated macrophages; CTLA-4, cytotoxic T-lymphocyte associated antigen-4; PD-1, Programmed cell death protein 1; PD-L, programmed death-ligand1; TIM-3, T-cell immunoglobulin (Ig) and mucin-domain containing protein-3; IEXs, immune cell-derived exosomes; TEXs, tumor-derived exosomes.

Hydrogen sulfide attenuates induction and prevents progress of the 6-hydroxydopamine-induced Parkinsonism in rat through activation of ATP-sensitive potassium channels and suppression of ER stress.

PURPOSE: Studies argue in favor of hydrogen sulfide (H2S) as the next potent therapeutic agent for neurodegenerative diseases. In present study, we investigated the effect of long term treatment with NaHS (as donor of H2S) on induction and progress of the 6-hydroxydopamine (6-OHDA) -induced Parkinsonism in rat. METHODS: The 6-OHDA was injected into medial forebrain bundle of right hemisphere by stereotaxic surgery. Behavioral tests and treatments were carried out to eight weeks after the toxin. Immunohistochemistry and western blotting were carried out to evaluate the survival of tyrosine hydroxylase (TH) -positive neurons in substantia nigra (SN) and also expression of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP), the markers of endoplasmic reticulum (ER) stress, in striatum and SN. RESULTS: Eight weeks assessment of the behavioral symptoms showed that NaHS especially at dose of 100 µmol/kg attenuates remarkably induction of the Parkinsonism and prevents its progress. NaHS also increased the survival of TH- positive neurons and suppressed 6-OHDA- induced overexpression of GRP78 and CHOP. Blockade of ATP-sensitive potassium (K-ATP) channels with glibenclamide (Glib) prevented markedly the effect of NaHS on both the induction phase and survival of TH- positive neurons. But Glib did not affect the preventing effect of NaHS on the progress phase and its suppressing effect on the overexpression of ER stress markers. CONCLUSION: H2S attenuates induction of the 6-OHDA- induced Parkinsonism and also increases the survival of dopaminergic neurons through activation of K-ATP channels. H2S also prevents progress of the Parkinsonism probably through suppression of ER stress.

Dexmedetomidine attenuates the induction and reverses the progress of 6-hydroxydopamine- induced parkinsonism; involvement of KATP channels, alpha 2 adrenoceptors and anti-inflammatory mechanisms.

BACKGROUND: Studies have shown that dexmedetomidine (DEX), a potent α2-adrenoceptors agonist provides neuroprotection through suppression of inflammatory response. In present study, we examined effect of DEX and its underlying mechanisms on the induction and progress of 6-OHDA- induced Parkinsonism in rat. MATERIAL AND METHODS: The 6-OHDA was injected into the medial forebrain bundle of right hemisphere by stereotaxic surgery and then, behavioral tests carried out within second, fourth, sixth and eighth weeks post-surgery. All treatments were started before the toxin and continued to eight weeks afterwards. Striatal levels of dopamine, TNF-α and IL-6 were measured within the eighth week after the toxin by enzyme-linked immunosorbent assay kits. RESULTS: DEX at dose of 50 µg/kg attenuated significantly the intensity of 6-OHDA- induced behavioral symptoms in the second week post-surgery. DEX also attenuated remarkably 6-OHDA- induced reduction in striatal dopamine level. These effects were also observed in rats treated by both DEX and yohimbine (YOH), a selective α2-adrenoceptors antagonist but were not observed in rats treated by both of DEX and glibenclamide (Glib), an ATP-sensitive potassium (KATP) channels blocker. DEX also reversed the progressive increase in intensity of the behavioral symptoms and reversed 6-OHDA- induced overproduction of TNF-α and IL-6. These effects were reversed by YOH but not Glib. CONCLUSION: Our findings indicate that DEX attenuates the induction and reverses the progress of 6-OHDA- induced Parkinsonism through activation of KATP channels and α2-adrenoceptors, respectively. Through activation of α2-adrenoceptors, DEX also exerts anti-inflammatory effect which is possibly another mechanism underlying the DEX's antiparkinsonism effect.