Targeting Methionine Addiction of Cancer Cells with Methioninase

Pokrovsky, Vadim S.; Qoura, Louay Abo; Demidova, Elena A.; Han, Qinghong; Hoffman, Robert M.

doi:10.1134/s0006297923070076

Cited by 8 publications

(7 citation statements)

References 45 publications

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“…The present study suggests that methionine restriction is promising in combination with second-line chemotherapy for metastatic breast cancer and further clinical studies are needed. o-rMETase is effective as it targets the fundamental basis of cancer, methionine addiction (6)(7)(8)(9)(10)(11)(12)(13)(14)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53).…”

Section: Discussionmentioning

confidence: 99%

Reduction of Tumor Biomarkers from very High to Normal and Extensive Metastatic Lesions to Undetectability in a Patient With Stage IV HER2-positive Breast Cancer Treated With Low-dose Trastuzumab Deruxtecan in Combination With Oral Recombinant Methioninase and a Low-methionine Diet

SATO,

HAN,

MORI

et al. 2024

Anticancer Res

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Background/Aim: Breast cancer is the most common and the deadliest cancer among women in the world. Treatment options for HER2-positive metastatic breast cancer patients are limited. Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC), has recently been introduced as second-line chemotherapy for HER2-positive metastatic breast cancer. The aim of the present study was to evaluate the efficacy of methionine restriction with oral recombinant methioninase (o-rMETase) and a low-methionine diet combined with T-DXd, on a patient with HER2-positive recurrent stage Ⅳ breast cancer. Case Report: A 66-year-old female was diagnosed with HER2-positive metastatic breast cancer. Computed tomography (CT) indicated peritoneal dissemination, thickening of the sigmoid colon and splenic flexure and widespread bone metastases. The patient was previously treated with fulvestrant, trastuzumab, pertuzumab, paclitaxel and capecitabine which were ineffective. T-DXd was administered as a second-line chemotherapy. Since the patient experienced strong side effects, the dose of T-Dxd was decreased. The patient began methionine restriction using o-rMETase and a low-methionine diet along with T-DXd. After the start of the combined treatment, CA15-3 and CA27.29, tumor markers for breast cancer, decreased rapidly from a very high level. The levels of both tumor markers are currently normal. Additionally, peritoneal-dissemination nodules, ascites and the thickness of the sigmoid colon and splenic flexure are no longer detected on CT. The patient maintains a high performance status, without severe side effects of the combination treatment. Conclusion: Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with T-DXd as second-line chemotherapy, was highly effective in a patient with HER2positive stage IV breast cancer.

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Section: Discussionmentioning

confidence: 99%

Reduction of Tumor Biomarkers from very High to Normal and Extensive Metastatic Lesions to Undetectability in a Patient With Stage IV HER2-positive Breast Cancer Treated With Low-dose Trastuzumab Deruxtecan in Combination With Oral Recombinant Methioninase and a Low-methionine Diet

SATO,

HAN,

MORI

et al. 2024

Anticancer Res

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“…The present study indicates the possibility of reducing the dose of IRN, without attenuating its efficacy, by combining it with rMETase, and provides an improved therapeutic opportunity for patients with colon cancer. rMETase is effective since it targets the fundamental and general hallmark of cancer, methionine addiction (6)(7)(8)(9)(10)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60).…”

Section: Discussionmentioning

confidence: 99%

Recombinant Methioninase Decreased the Effective Dose of Irinotecan by 15-fold Against Colon Cancer Cells: A Strategy for Effective Low-toxicity Treatment of Colon Cancer

SATO,

HAN,

KUBOTA

et al. 2023

Anticancer Res

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Background/Aim: Irinotecan (IRN), a topoisomerase I inhibitor and pro-drug of , is first-line treatment of colon cancer as part of FOLFIRI and FOLFOXIRI combination chemotherapy. However, IRN causes dose-limiting adverse events such as neutropenia and diarrhea. Dose reductions are sometimes required, which reduce efficacy. Recombinant methioninase (rMETase) targets the fundamental basis of cancer, methionine addiction, known as the Hoffman effect, and enhances the efficacy of numerous chemotherapy drugs. The present study determined the efficacy of rMETase when administered in combination with IRN. Materials and Methods: Cell viability was assessed by cultivating the HCT-116 human colorectal cancer cell line in 96-well plates at 1×10 3 cells per well in Dulbecco's modified Eagle's medium (DMEM). Subsequently, HCT-116 cells were treated with increasing concentrations of SN-38, the active form of IRN, ranging from 0.5 nM to 32 nM, and/or rMETase ranging from 0.125 to 8 U/ml. After treatment for 72 h, the half-maximal inhibitory concentration (IC 50 ) of SN-38 alone and rMETase alone for HCT-116 cells were determined. Using the IC 50 concentration of rMETase, we determined the IC 50 of SN-38 in combination with rMETase. Cell viability was determined with the cell-counting Kit-8 with the WST-8 reagent.. Results: The IC 50 of rMETase alone for the HCT-116 cells was 0.55 U/ml, and the IC 50 of IRN (SN-38) alone was 3.50 nM. rMETase at 0.55 U/ml lowered the IC 50 of SN-38 to 0.232 nM (p<0.0001), a 15-fold reduction. Conclusion: rMETase and IRN are strongly synergistic, giving rise to the possibility of lowering the effective dose of IRN for the treatment of patients with colon cancer, thereby reducing its severe toxicity. This new strategy will allow more patients with cancer to be effectively treated with IRN.Irinotecan (IRN) is a prodrug of SN-38 and exerts its efficacy by inhibiting topoisomerase I, which is required for DNA replication (1,2). IRN has been used as first-or secondline chemotherapy for over 20 years for a variety of cancers, including gastrointestinal, gynecological, and respiratory cancer (3). In particular, IRN has become first-line treatment for colorectal cancer with unresectable distant metastases (4). However, toxicity such as neutropenia and diarrhea, is a dose-limiting factor of IRN. Appropriate management of adverse effects, including dose reduction, is essential for the use of IRN, but reduces efficacy (3, 5).All cancer cell types are addicted to methionine (6, 7) due at least partially to elevated levels of abnormal transmethylation (8-10). Methionine addiction, termed the Hoffman effect (9), is much stronger than the Warburg effect for glucose addiction (11). Methionine restriction (MR) has been observed to selectively arrest the cell cycle of cancer cells, specifically in the late-S/G 2 phase (12, 13), a target of most chemotherapy drugs (14-17). However, methionine is present in many types of food and its restriction through dietary means alone is a challenge (18-21). Our laboratory has d...

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“…However, tumor cells are incapable of utilizing Hcy to synthesize Met for several reasons, with the leading cause being the ineffectiveness of the Met synthase enzyme in cancer cells. Thus, tumor cells are more sensitive to the MR environment [60,[62][63][64]. Nevertheless, our comprehension of the role of Met metabolism in cancer remains at an early stage due to its intricate nature.…”

Section: Mechanisms Of Met In the Pathophysiology Of Gastric Cancermentioning

confidence: 99%

“…Thus, in theory, MR could augment the efficacy of chemotherapeutic drugs for treating cancer. A growing body of research has demonstrated that MR can synergistically interact with various chemotherapeutic agents; for instance, cancer cells in Met − /Hcy+ medium selectively arrested in the S/G2 phase and furthermore eliminated clonogenic cells and rendered cancer cells sensitive to cell-cycle-specific drugs [64], including 5-fluorouracil [136], gemcitabine [137], cisplatinum [52], Doxorubicin (DOX), Vincristine (VCR) [138], and so on. In addition to inducing the chemo-sensitive S/G2 phase, MR has the potential to augment the efficacy of chemotherapeutic agents through alternative pathways.…”

Section: The Role and Mechanism Of Met In Gastric Cancer Chemotherapymentioning

confidence: 99%

The Role of Methionine Restriction in Gastric Cancer: A Summary of Mechanisms and a Discussion on Tumor Heterogeneity

Zou,

Yuan,

Zhou

et al. 2024

Biomolecules

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Gastric cancer is ranked as the fifth most prevalent cancer globally and has long been a topic of passionate discussion among numerous individuals. However, the incidence of gastric cancer in society has not decreased, but instead has shown a gradual increase in recent years. For more than a decade, the treatment effect of gastric cancer has not been significantly improved. This is attributed to the heterogeneity of cancer, which makes popular targeted therapies ineffective. Methionine is an essential amino acid, and many studies have shown that it is involved in the development of gastric cancer. Our study aimed to review the literature on methionine and gastric cancer, describing its mechanism of action to show that tumor heterogeneity in gastric cancer does not hinder the effectiveness of methionine-restricted therapies. This research also aimed to provide insight into the inhibition of gastric cancer through metabolic reprogramming with methionine-restricted therapies, thereby demonstrating their potential as adjuvant treatments for gastric cancer.

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Targeting Methionine Addiction of Cancer Cells with Methioninase

Cited by 8 publications

References 45 publications

Reduction of Tumor Biomarkers from very High to Normal and Extensive Metastatic Lesions to Undetectability in a Patient With Stage IV HER2-positive Breast Cancer Treated With Low-dose Trastuzumab Deruxtecan in Combination With Oral Recombinant Methioninase and a Low-methionine Diet

Reduction of Tumor Biomarkers from very High to Normal and Extensive Metastatic Lesions to Undetectability in a Patient With Stage IV HER2-positive Breast Cancer Treated With Low-dose Trastuzumab Deruxtecan in Combination With Oral Recombinant Methioninase and a Low-methionine Diet

Recombinant Methioninase Decreased the Effective Dose of Irinotecan by 15-fold Against Colon Cancer Cells: A Strategy for Effective Low-toxicity Treatment of Colon Cancer

The Role of Methionine Restriction in Gastric Cancer: A Summary of Mechanisms and a Discussion on Tumor Heterogeneity

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