Killing effect of methionine enkephalin on melanoma in vivo and in vitro

Abstract

Melanoma is a common cutaneous malignancy, that is also found in specific mucosal sites, and is associated with a poor prognosis. The aim of the present study was to investigate the cytotoxicity of methionine enkephalin (MENK) for B16 melanoma cells in vivo and in vitro. The results of the present study allowed our conclusion that MENK regulates the proliferation of B16 cells, causing cell cycle arrest in the G0/G1 phase and a decrease in the percentage of cells in the S and G2/M phases. Reverse transcription-quantitative polymerase chain reaction demonstrated that MENK increased opioid receptor expression in the B16 cells. Furthermore, the tumor volume and weight in the MENK-treated group were lower than those in the control group (NS) and MENK and naltrexone (NTX)-treated groups. MENK exerted both significant antitumor activity on the growth of B16 cells and a longer survival time in mice. The mice treated with MENK exhibited an increased ratio of CD4+ to CD8+ T cells as tested by flow cytometry (FCM), resulting in a ratio of 2.03 in the control group, 3.69 in the MENK-treated group, and 2.65 in the MENK and NTX group. Furthermore, a significant increase in plasma levels of IL-2, IFN-γ and TNF-α was revealed as assessed by ELISA. In conclusion, the results of the present study indicate that MENK has a cytotoxic effect on B16 melanoma cells in vitro and in vivo, and suggest a potential mechanism for these bioactivities. Therefore, we posit that MENK should be investigated, not only as a primary therapy for melanoma, but also as an adjuvant therapy in combination with chemotherapies.

Scorpion Venom Antimicrobial Peptides Induce Caspase-1 Dependant Pyroptotic Cell Death

“…Although AMPs have been shown to act by a variety of diverse mechanisms, both within the membrane and in the cytoplasm and cell nucleus ( Graf and Wilson, 2019 ; Haney et al, 2019 ; Zasloff, 2019 ), all AMPs, as positively charged amphipathic molecules are initially targeted to the cell membrane through electrostatic interactions. Some AMPs can exploit both differences in membrane charge and cell stability to specifically target certain cancer cells ( Rathinakumar et al, 2009 ; Mahlapuu et al, 2016 ; Wang et al, 2017 ), suggesting that these peptides are potential new anti-cancer agents and encouraging the further development of other classes of AMPs in this area.…”

“…Some AMPs can exploit both differences in membrane charge and cell stability to specifically target certain cancer cells ( Rathinakumar et al, 2009 ; Mahlapuu et al, 2016 ; Wang et al, 2017 ), suggesting that these peptides are potential new anti-cancer agents and encouraging further development of other classes of AMPs in this area. When examining the effects of Smp24 and Smp43 in morphological studies ( Elrayess et al, 2019 ), we found suggestive evidence of pyroptosis.…”

Characterization of Union Sites for Opioids in Human Lymphocyte Membranes

“…It has been shown that OP regulate NKCA [17,42]. NK cells have generated increasing interest due to their potential role in hematopoiesis and in the control of viral infections, as well as in the growth of some types of tumors and in the extracellular destruction of bacteria [43,44]. Although several agents capable of positively or negatively altering NKCA have been described, the mechanism by which this process develops is not completely clear.…”

“…similar in both cases studied. On the other hand, when the lymphocytes were treated with concentrations higher than the physiological ones, a response greater than 25% of the control value was obtained, even though this stimulation is not present in the total of the samples analyzed and no dependence was observed on the age or sex of the individual studied Probably the individual diversity of the samples as well as to the high heterogeneity existing in the NK cells, since it has been described that they form at least three subpopulations of functionally distinct cells: effector cells capable of binding and destroying the target cell and two non-cytolytic subpopulations, one capable and the other incapable of joining the target cell [43,51]. Our results and the fact that Naloxone inhibits the increase in NKCA mediated by both IL-2 and IFN-α [47,52] it would be expected to have the existence of opioid receptors in NK cells, both due to the stimulation achieved as per the relationship between OP and Naloxone.…”

Neuroendocrine Factors in Melanoma Pathogenesis

“…The authors recorded growth restriction after the application of 50 µg of MENK for 1–2 weeks, which was countered by naloxone, confirming the opioid receptor involvement [ 283 ]; these effects were obtained via both direct cytotoxicity on melanoma cells as well as through immune response modulation. Using the same animal model, Wang et al have identified that MENK augments OGFr expression, causes cell cycle arrest, and increases the ratio of CD4+/CD8+ T cells as well as plasma levels of various cytokines including IL-2, TNF-α, and interferon-γ [ 284 ]. These effects increase survival while limiting tumor growth and dissemination.…”