Immunotherapy of cancer via mediation of cytotoxic T lymphocytes by methionine enkephalin (MENK)

Li, Weiwei; Chen, Wenna; Herberman, Ronald B.; Plotnikoff, Nicolas P.; Youkilis, Gene; Griffin, Noreen; Wang, Enhua; Lu, Cuihua; Shan, Fengping

doi:10.1016/j.canlet.2013.10.029

Cited by 45 publications

(20 citation statements)

References 42 publications

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“…First, the sizes and weights of tumor tissues were measured. Strikingly, the weight and size were decreased significantly in MENK treated group compared with those in the normal saline group, which was consistent with the previous results, [7][8][9] (Fig. 4), reconfirming the antitumor effect of MENK in vivo.…”

Section: Menk Decreased the Tumor Growth And Suppressed The Splenic Csupporting

confidence: 91%

“…29 MENK, the endogenous neuropeptide, appears to be useful in immune responses against tumors by up-regulation of CD8CT cells' activity; down-regulation macrophage polarization from M2 to M1 type; induction dendritic cell maturation to initiate T cells responds and to intensify CD4CT cells functions as well as the secretion of various cytokines. [7][8][9] In current study we provide evidence that MENK attenuates TGF-binduced conversion of CD4CCD25-T cells to CD4CCD25CTregs in vitro and that MENK affects Tregs in spleen and TDLN in S180 mice model. Several important conclusions can be drawn from the current work.…”

Section: Discussionsupporting

confidence: 52%

“…Studies in cancer patients treated with MENK demonstrated regression in tumor incidence, retardation in tumor progression and prolonged survival. [4][5][6] Since 2010 our research team has published quite some of data elucidating the role of MENK in coordinating cells in immune system, as evidenced by: (1) dendritic cells (DCs) treated with MENK could up-regulate expressions of opioid receptors (delta and kappa), and positively regulate functions of CD8CT cells; 7 (2) MENK could induce the influx of Ca 2C on CD8CT cells, leading to translocation of NFAT2 into the nucleus, consequently followed by expansion of CD8CT cells and the development of anti-tumor CTLs; 8 (3) MENK participates in innate immunity against tumors by reversing macrophages polarization from M2 to M1, which consequently enhances macrophages to kill tumor cells as well as produce Th1 cytokines; 9 (4) MENK could intensify the pathway of DC-CD4CT cells and (5) MENK could improve antitumor activity of DC loaded with tumor antigen. More importantly, our team finds that MENK shows strong inhibition to Treg in peripheral blood of normal donors and cancer patients.…”

Section: Introductionmentioning

confidence: 99%

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Methionine Enkephalin (MENK) Inhibits tumor growth through regulating CD4+Foxp3+ Regulatory T cells (Tregs) in mice

Meng

Plotnikoff³

et al. 2015

Cancer Biology & Therapy

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Methionine enkephalin (MENK), an endogenous neuropeptide, plays an crucial role in both neuroendocrine and immune systems. CD4+Foxp3+ regulatory T cells (Tregs) are identified as a major subpopulation of T lymphocytes in suppressing immune system to keep balanced immunity. The aim of this research work was to elucidate the mechanisms via which MENK interacts with Tregs in cancer situation. The influence of MENK on transforming growth factor-β (TGF-β) mediated conversion from naïve CD4+CD25- T cells to CD4+CD25+ Tregs was determined and the data from flow cytometry (FCM) analysis indicated that MENK effectively inhibited the expression of Foxp3 during the process of TGF-βinduction. Furthermore, this inhibiting process was accompanied by diminishing phosphorylation and nuclear translocation of Smad2/3, confirmed by western blot (WB) analysis and immunofluorescence (IF) at molecular level. We established sarcoma mice model with S180 to investigate whether MENK could modulate Tregs in tumor circumstance. Our findings showed that MENK delayed the development of tumor in S180 tumor bearing mice and down-regulated level of Tregs. Together, these novel findings reached a conclusion that MENK could inhibit Tregs activity directly and retard tumor development through down-regulating Tregs in mice. This work advances the deepening understanding of the influence of MENK on Tregs in cancer situation, and relation of MENK with immune system, supporting the implication of MENK as a new strategy for cancer immunotherapy.

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Section: Menk Decreased the Tumor Growth And Suppressed The Splenic Csupporting

confidence: 91%

Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

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Methionine Enkephalin (MENK) Inhibits tumor growth through regulating CD4+Foxp3+ Regulatory T cells (Tregs) in mice

Meng

Plotnikoff³

et al. 2015

Cancer Biology & Therapy

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“…The mechanistic pathways of LDN are unclear. Some investigations suggest that LDN works directly as an immunomodulating agent [68,69], whereas other studies on T and B cell proliferation in vitro [70,71] and in vivo [72] have demonstrated that the modulation of the immune system most likely is a direct response to increased or decreased proliferation and activation of peripheral lymphocytes and resultant cytokine production.…”

Section: Intermittent Ogfr Blockade: Treatment Of Autoimmune Disordersmentioning

confidence: 96%

Duration of opioid receptor blockade determines biotherapeutic response

McLaughlin

Zagon

2015

Biochemical Pharmacology

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“…В эксперименте Мет-энкефалин тормозит рост опухолей (в частности за счет модулирования активности регуляторных Т-клеток типа CD4+/Foxp3+, поддерживающих баланс между иммуно-супрессией и иммунным реагированием) [10]. Иммуноте-рапевтические эффекты Мет-энкефалина также осущест-вляются за счет активации цитотоксических Т-лимфоцитов CD8+T, имеющих опиоидные рецепторы на клеточной мембране [11].…”

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Evaluation of the antitumor potential of cerebrolysin

Gromova

Пронин

Torshin

et al. 2016

Z. nevrol. psikhiatr. im. S.S. Korsakova

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Препарат церебролизин, основой которого является высокоочищенный экстракт пептидов головного мозга молодых свиней, успешно используется в клинической практике для восстановления неврологических функций пациентов с инсультом, деменцией и черепно-мозговой травмой. Известно, что применение церебролизина до-стоверно уменьшает неврологический дефицит [1], сни-жает объем зоны инфаркта при инсульте [2], оказывает нейрорегенеративное [3], противоспалительное и антиок-сидантное действие [4,5]. Также на модели у животных (крысы линии Вистар) тиосемикарбазидовых судорог бы-ло показано, что церебролизин обладает противосудорож-ными эффектами [6]. Цель исследования. изучение влияния церебролизина на рост и метастазирование злокачественных новообразований у мышей (модель карциномы легких льюис). Материал и методы. исследование проведено на 60 самцах мышей-гибридов F 1 (возраст 2-2,5 мес, масса тела 19-22 г). В качестве опухолевой модели использована перевиваемая эпидермоидная карцинома легких льюис (Клл) -стандартная экспериментальная модель для оценки свойств потенциальных противоопухолевых средств. Животным со 2 по 16-е сутки после трансплантации опухоли ежедневно вводили церебролизин путем однократной внутрибрюшинной инъекции в дозах 524 мг/кг (n=20) и 1800 мг/кг (n=20). Результаты и заключение. По сравнению с контрольной группой (n=20) отмечено торможение роста Клл в период проведения терапии (с 7 по 16-е сутки). Воздействие препарата сопровождалось торможением скорости роста опухоли на 10-15% (р<0,05). Установлен дозозависимый эффект снижения числа крупных метастазов: с повышением дозы церебролизина число крупных метастазов статистически значимо снижалось на 30-50% (р=0,01). Сделан вывод, что церебролизин достоверно подавляет интенсивность роста карциномы легких льюис. Objective. To investigate the effect of cerebrolysin on the growth and metastasis of malignant tumors in mice (a model of lung carcinoma lewis). Material and methods. The study was performed on 60 male mice, hybrids F1 (the age of 2-2.5 months, body weight 19-22g.). Transplantable epidermoid lewis lung carcinoma (llC) was used as a standard experimental model to evaluate the properties of the potential antitumor agents. experimental animals were administered a single intraperitoneal injection of cerebrolysin in doses of 524 mg/kg (n=20) and 1800 mg/kg (n=20) daily from 2 to 16 days after tumor transplantation. Results and conclusion. Compared with the control group (n=20), cerebrolysin induced growth inhibition of llC during the treatment (7 to 16 days). An impact of the drug was accompanied by the inhibition of the tumor growth rate by 10-15% (p<0.05). Cerebrolysin demonstrated a dose-dependent effect of reducing the large number of metastases: a number of large metastases significantly decreased by 30-50% with the increase of cerebrolysin dose (p=0.01). Cerebrolysin can significantly suppress the growth rate of lewis lung carcinoma.

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Immunotherapy of cancer via mediation of cytotoxic T lymphocytes by methionine enkephalin (MENK)

Cited by 45 publications

References 42 publications

Methionine Enkephalin (MENK) Inhibits tumor growth through regulating CD4+Foxp3+ Regulatory T cells (Tregs) in mice

Methionine Enkephalin (MENK) Inhibits tumor growth through regulating CD4+Foxp3+ Regulatory T cells (Tregs) in mice

Duration of opioid receptor blockade determines biotherapeutic response

Evaluation of the antitumor potential of cerebrolysin

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