Oral Recombinant Methioninase Prevents Obesity in Mice on a High-fat Diet

Tashiro, Yoshihiko; Han, Qinghong; Tan, Yuying; Sugisawa, Norihiko; Yamamoto, Jun; Nishino, Hiroto; Inubushi, Sachiko; Higuchi, Takashi; Aoki, Takeshi; Murakami, Masahiko; Hoffman, Robert M.

doi:10.21873/invivo.11799

Cited by 16 publications

(17 citation statements)

References 31 publications

(43 reference statements)

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“…rMETase can be used clinically as an effective oral supplement (35). o-rMETase is very effective for methionine depletion in the plasma of patients (35) and mice (10,13,36), and has many benefits, especially the lack of immunological reactions, compared to injected rMETase (37).…”

Section: Discussionmentioning

confidence: 99%

Adjuvant Oral Recombinant Methioninase Inhibits Lung Metastasis in a Surgical Breast-Cancer Orthotopic Syngeneic Model

et al. 2020

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Background/Aim: In the present study, we evaluated the efficacy of adjuvant administration of oral recombinant methioninase (o-rMETase) against recurrence and metastasis in a 4T1 murine breast-cancer syngeneic model. Materials and Methods: 4T1 cells were orthotopically implanted into the 2nd mammary fat pad of BALB/c mice. The 4T1 orthotopic syngeneic models were randomized into 2 groups after primary tumor resection: untreated control and o-rMETase (100 units, oral, daily, 2 weeks). Results: The frequency and extent of local recurrence were reduced by o-rMETase. The number of individual cancer cells and metastatic nodules on the lung surface was significantly lower in the o-rMETase-treated mice than the untreated control mice. Conclusion: Adjuvant o-rMETase inhibited local recurrence and lung metastasis after primary tumor resection. Methionine addiction is possibly the most fundamental and general hallmark of cancer (1-9) and is tightly linked to other hallmarks of cancer (2). Methionine addiction was discovered in our laboratory and is due to increased rates of transmethylation compared to normal cells (3-6). Methionine overuse by cancer cells is called the "Hoffman effect", analogous to the "Warburg effect" of glucose overuse by cancer cells (7). Methionine restriction targets the methionine addiction of cancer. For methionine restriction, we have used L-methionine-deamino-mercapto-methanelyase (methioninase) (8, 9). Recombinant methioninase (rMETase) has been produced in Escherichia coli containing the methioninase gene cloned from Pseudomonas putida (9). We have reported the efficacy of oral administration of rMETase (o-rMETase) on various types of tumors in vivo, including patient-derived orthotopic xenograft (PDOX) mouse models (10-16). Breast cancer needs follow-up for long periods after treatment. Although distant recurrence can be detected mostly in the first 5 years, there is still a significant rate of recurrence in the second and the third 5-year periods (17, 18). In order to reduce recurrence and improve survival, systemic adjuvant therapy is administered as the standard of care. Adjuvant endocrine therapy for at least 5 years is recommended for patients with hormone receptor-positive breast cancer (19, 20). Oral endocrine therapy is tolerable long term. However, patients with hormone receptor-negative breast cancer are recommended to take one regimen of adjuvant chemotherapy after surgery and be frequently followed-up for over 5-years. If a novel treatment, tolerable for 5 years, decreases the recurrence rate, it would be recommended for patients with hormone receptor-negative breast cancer. Murine breast cancer cell lines have been used to generate orthotopic syngeneic models (21-25), especially the 4T1 cell line which has the characteristics of human triple-negative breast cancer (TNBC) and is highly metastatic (21-24). Additionally, the lung is the most frequent site for metastasis in 4T1 orthotopic models. In the present study, we evaluated the efficacy of adjuvant o-rMETase on local recurrenc...

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Section: Discussionmentioning

confidence: 99%

Adjuvant Oral Recombinant Methioninase Inhibits Lung Metastasis in a Surgical Breast-Cancer Orthotopic Syngeneic Model

et al. 2020

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“…(93) Hepatic lipids were also reduced in male mice after rMETase treatment, suggesting a role for this intervention in preventing fatty liver and obesity in rodents. (93) However, no clear evidence has been offered regarding the duration of effects caused by this intervention, and what side effects there may be, bringing attention to the need for more studies in this area. It is nevertheless confirmation that decreasing the levels of methionine, either through dietary or pharmacological interventions, may be a promising and achievable way of preventing the onset of diabetes and obesity, and improving overall metabolic health, thus health span.…”

Section: Methionine Restriction and Diabetesmentioning

confidence: 95%

“…An alternative, pharmacological approach has also been employed to simulate dietary MR. In vivo studies with an oral recombinant methioninase, which catabolised methionine to α-ketobutyrate and ammonia, have been shown to prevent diet-induced obesity, increase glucose tolerance and decrease fat mass in mice fed a high-fat diet (93) . Hepatic lipids were also reduced in male mice after recombinant methioninase treatment, suggesting a role for this intervention in preventing fatty liver and obesity in rodents (93) .…”

Section: Methionine Restriction and Diabetesmentioning

confidence: 99%

“…In vivo studies with an oral recombinant methioninase, which catabolised methionine to α-ketobutyrate and ammonia, have been shown to prevent diet-induced obesity, increase glucose tolerance and decrease fat mass in mice fed a high-fat diet (93) . Hepatic lipids were also reduced in male mice after recombinant methioninase treatment, suggesting a role for this intervention in preventing fatty liver and obesity in rodents (93) . However, no clear evidence has been offered regarding the duration of effects caused by this intervention, and what side effects there may be, bringing attention to the need for more studies in this area.…”

Section: Methionine Restriction and Diabetesmentioning

confidence: 99%

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Effects of dietary restriction on metabolic and cognitive health

2020

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Life expectancy in most developed countries has been rising over the last century. In the UK alone, there are around 12 million people over 65 years old and centenarians have increased by 85% in the past 15 years. As a result of our ageing population, which is due mainly to improvements in medical treatments, public health, improved housing and lifestyle choices, there is an associated increase in prevalence of pathological conditions, such as metabolic disorders, type 2 diabetes (T2D), cardiovascular and neurodegenerative diseases, many types of cancer and others. Statistics suggest that nearly 54% of elderly people in the UK live with at least two chronic conditions, revealing the urgency for identifying interventions that can prevent and/or treat such disorders. Nonpharmacological, dietary interventions such as caloric restriction (CR) and methionine restriction (MR) have revealed promising outcomes in increasing longevity and preventing and/or reversing the development of ageing-associated disorders. In this review, we discuss the evidence and mechanisms that are involved in these processes. FGF21 and H 2 S are important molecules involved in the effects of CR and MR in the extension of life span. Their role is also associated with the prevention of metabolic and cognitive disorders, highlighting these interventions as promising modulators for improvement of health span.

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“…Numerous studies have shown that oral methioninase is highly effective as an antitumor drug in mouse models of cancer (26,27). Oral administration of methioninase resulted in 80% depletion of methionine within 3 h (28). Oral methioninase restricts methionine in the gut and does not enter the blood stream, thereby eliminating immunological problems (28).…”

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confidence: 99%

Oral Methioninase for Covid-19 Methionine-restriction Therapy

Hoffman

Han

2020

In Vivo

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The Covid-19 pandemic is a world-wide crisis without an effective therapy. While most approaches to therapy are using repurposed drugs that were developed for other diseases, it is thought that targeting the biology of the SARS-CoV-2 virus, which causes Covid-19, can result in an effective therapeutic treatment. The coronavirus RNA cap structure is methylated by two viral methyltransferases that transfer methyl groups from S-adenosylmethionine (SAM). The proper methylation of the virus depends on the level of methionine in the host to form SAM. Herein, we propose to restrict methionine availability by treating the patient with oral recombinant methioninase, aiming to treat Covid-19. By restricting methionine we not only interdict viral replication, which depends on the viral RNA cap methyaltion, but also inhibit the proliferation of the infected cells, which have an increased requirement for methionine. Most importantly, the virallyinduced T-cell-and macrophage-mediated cytokine storm, which seems to be a significant cause for Covid-19 deaths, can also be inhibited by restricting methionine, since T-cell and macrophrage activation greatly increases the methionine requirement for these cells. The evidence reviewed here suggests that oral recombinant methioninase could be a promising treatment for coronavirus patients.Coronavirus SARS-CoV-2 is responsible for the world-wide pandemic of Covid-19. At the present time there is no effective documented therapy. "Repurposed" drugs such as Kalera, a mixture of lopinavir and ritonvir, used as protease inhibitors for HIV and SARS, failed in a clinical trial for Covid-19 in China (1). Hydroxychloroquine, a malaria drug, also failed in a recent clinical trial in China (2). Ramdesivir an adenosine analog tested for Ebola on monkeys is being tested for Covid-19 (3). The in vitro activity of ramdesivir and hydroxychloroquine against SARS-CoV-2 is at micro-molar concentrations, which are quite high, indicating possible toxicity in vivo ( 4). An influenza drug called Arbidol (umifenovir) was not able to improve the clinical outcome of Covid-19 patients in China (5). Arbidol is an inhibitor that blocks the fusion of the influenza virus with the cell and is active against coronavirus in vitro (5). Tocilizumab (6), which targets the IL-6 receptor, is being tested for Covid-19-induced cytokine storm. A mesenchymal stem-cell therapy is also being tested for Covid-19 (7).SARS-Cov-2 is a positive single-stranded RNA virus which uses its genomic RNA both for translation and replication (8-11). For proper RNA replication and translation, the cap of the viral RNA must be methylated (8-14). It appears that two methylation sites are present in the viral RNA of coronaviruses; one site is necessary for replication and translation, and the other site possibly for the viral RNA to evade the host intracellular immunity system which would degrade the RNA if not for the cap methylation (8-14). For example, Wang et al. showed that a designed peptide named TP29 targeted the 2'-Omethyltransferase of co...

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Oral Recombinant Methioninase Prevents Obesity in Mice on a High-fat Diet

Cited by 16 publications

References 31 publications

Adjuvant Oral Recombinant Methioninase Inhibits Lung Metastasis in a Surgical Breast-Cancer Orthotopic Syngeneic Model

Adjuvant Oral Recombinant Methioninase Inhibits Lung Metastasis in a Surgical Breast-Cancer Orthotopic Syngeneic Model

Effects of dietary restriction on metabolic and cognitive health

Oral Methioninase for Covid-19 Methionine-restriction Therapy

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