Oral Recombinant Methioninase, Combined With Oral Caffeine and Injected Cisplatinum, Overcome Cisplatinum-Resistance and Regresses Patient-derived Orthotopic Xenograft Model of Osteosarcoma

Higuchi, Takashi; Oshiro, Hiromichi; Miyake, Kentaro; Sugisawa, Norihiko; Han, Qinghong; Tan, Yuying; Park, Junho; Zhang, Zhiying; Razmjooei, Sahar; Yamamoto, Norio; Hayashi, Katsuhiro; Kimura, Hiroaki; Miwa, Shinji; Igarashi, Kentaro; Bouvet, Michael; Chawla, Sant P.; Singh, Shree Ram; Tsuchiya, Hiroyuki; Hoffman, Robert M.

doi:10.21873/anticanres.13646

Cited by 30 publications

(36 citation statements)

References 14 publications

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“…Our laboratory has recently developed oral rMETase (o-rMETase) which has been shown to be highly effective in mouse models of cancer as injectable o-rMETase (20)(21)(22)(23)(24)(25)(26)(27). In the present report, we show that o-rMETase prevents obesity in mice on a high-fat diet, thereby opening a new paradigm for obesity prevention.…”

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confidence: 55%

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

Tashiro

Han

Tan

et al. 2020

In Vivo

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Background/Aim: obesity is a world-wide recalcitrant problem leading to many diseases. Dietary methionine restriction (MR) has been shown to prevent obesity, but it is an onerous regimen. The present study aimed to determine the effects of oral recombinant methionase (o-rMETase), on preventing obesity in mice on a high-fat diet. Materials and Methods: Male C57BL/6J mice in the control group were fed a control diet (CD) (+6.5% fat) for 25 days, and others were fed a high-fat (HF) diet (+34.3% fat) for 25 days. Then, the mice were divided into three dietary groups: 1) HF + phosphate buffered saline (PBS) group; 2) HF + o-rMETase group; and 3) untreated non-HF group. Results: The mice on the CD increased in body weight by 14% during experimental period of 25 days; in contrast the mice in the HF+PBS group increased by 33%; however, the mice on the HF+o-rMETase group increased only by 14% (p=0.02,. Conclusion: The HF+ o-rMETase group had the same weight increase as untreated mice on a normal fat diet, demonstrating the potential for o-rMETase to eliminate the need for dieting to maintain normal body weight. 489

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confidence: 55%

“…Our laboratory developed rMETase from Pseudomonas putida, cloned in Escherichia coli, as a very efficient means of MR (16). A big advance was our laboratory's development of o-rMETase which makes administration safe and easy without side-effects (20,(21)(22)(23)(24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

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

Tashiro

Han

Tan

et al. 2020

In Vivo

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“…We also demonstrated that PDOX models maintain the original histological and molecular characteristics after transplantation in mice (16,17). PDOX models provide osteosarcoma patients with specific and individualized treatment options (18)(19)(20). We previously showed that PIO could overcome doxorubicin resistance in the PDOX model of osteosarcoma (4).…”

Section: Discussionmentioning

confidence: 84%

PPARγ Agonist Pioglitazone in Combination With Cisplatinum Arrests a Chemotherapy-resistant Osteosarcoma PDOX Model

Higuchi¹,

Yamamoto²,

Sugisawa³

et al. 2019

Cancer Genomics Proteomics

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Background/Aim: Cisplatinum (CDDP) is a firstline drug in osteosarcoma treatment and the acquisition of resistance to CDDP is associated with a poor prognosis. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor that plays important roles in cell proliferation, differentiation, development, metabolism and cell death. Recently, PPARγ was reported to enhance the efficacy, overcome resistance, and decrease the toxicity of CDDP in various human cancers. In this study we tested whether pioglitazone (PIO), a PPARγ agonist, could overcome CDDP resistance in osteosarcoma. Materials and Methods: In this study, we used a human osteosarcoma cell line and a patient-derived orthotopic xenograft (PDOX) models of osteosarcoma. We measured cell viability of 143B human osteosarcoma cells when treated with CDDP and PIO. We randomized PDOX models of osteosarcoma into four treatment groups: Group 1, Untreated control; Group 2, PIO alone; Group 3, CDDP alone; Group 4, a combination of CDDP and PIO. Each group comprised six mice. Mice were treated for 14 days and tumor size and body weight were measured. Results: Cell viability of 143B human osteosarcoma cells was significantly reduced when PIO (50 μmol/l) was combined with CDDP compared to CDDP alone. PDOX osteosarcoma tumors treated with the CDDP-PIO combination showed the strongest tumor growth inhibition compared to other treatment groups. PDOX osteosarcoma tumors treated with the CDDP-PIO combination had the least cancer cells and the most necrosis in histological section. Conclusion: These results suggest that combining PIO along with CDDP could be an effective treatment strategy for osteosarcoma and has important clinical potential for patients. Cisplatinum (CDDP) is first-line therapy for osteosarcoma. However, its use is limited due to side-effects, such as nephrotoxicity, neuropathies, and/or bone marrow toxicity (1). Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor superfamily. PPARγ plays important roles in cell proliferation and differentiation, lipid metabolism, development, and cell death and is a candidate tumor suppressor gene (2). PPARγ ligands exert anti-tumor efficacy in various cancer models, however, monotherapy of PPARγ ligands showed a limited efficacy in clinical trials (3). Even though PPARγ ligands are less efficacious as monotherapy, in combination with traditional chemotherapy drugs, they showed improved clinical potential (3). We previously showed that the PPARγ ligand pioglitazone (PIO) could overcome doxorubicin-resistance in an osteosarcoma patient-derived orthotopic xenograft (PDOX) model (4). It has been demonstrated that PPARγ ligands combined with platinum-based drugs increase therapeutic efficacy in multiple cancer models such as nonsmall cell lung cancer (5), colon cancer (6), and ovarian cancer (6), but not in osteosarcoma. In the present study, we tested whether PIO could overcome CDDP-resistance in osteosarcoma PDOX model.

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“…These results suggest the use of a higher dose of methioninase and combination with chemotherapy to further control loco-regional recurrence. Our previous studies have indicated that the combination of chemotherapy with methionine restriction is often highly effective (18)(19)(20)(21)(22)(23)(24)(25)36).…”

Section: Discussionmentioning

confidence: 99%

“…The results indicate that o-rMETase can be an effective treatment to inhibit recurrent tumor growth in TNBC, as a cancer-specific metabolism-targeted therapy. Our previous experiments have shown o-rMETase holds much promise (19)(20)(21)(22)(23)(24)(25)(36)(37)(38), as it is an oral drug, despite being a large tetrameric protein, with no known side effects. We recently published a study on the long-term treatment with o-rMETase of a patient with bone-metastatic prostate cancer (38).…”

Section: Discussionmentioning

confidence: 99%

Oral Methioninase Inhibits Recurrence in a PDOX Mouse Model of Aggressive Triple-negative Breast Cancer

Lim

Hamada

Yamamoto

et al. 2020

In Vivo

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Background/Aim: The aim of the study was to use a triple-negative breast cancer (TNBC) patient-derived orthotopic xenograft (PDOX) model to examine the efficacy of oral recombinant methioninase (o-rMETase) against this recalcitrant disease. Materials and Methods: The TNBC tumor from a patient was implanted in the right 4 th inguinal mammary fat pad of nude mice. Two weeks later, the mice underwent tumorectomy with grossly-negative surgical margins. Two days after tumorectomy the mice were divided in two groups: one control and one treated with o-rMETase. Results: Tumors recurred in all mice. On day 11, the mean recurrent tumor volumes were 936.7 mm 3 in the control group and 450.9 mm 3 in the o-rMETase group (p<0.05). On day 15, the mean recurrent tumor volumes were 3392.5 mm 3 in the control group and 1603.5 mm 3 in the o-rMETase group. The mean recurrent tumor weights were 2.1 g in the control group and 1.1 g in the o-rMETase group on day 15. Conclusion: o-rMETase is an effective adjuvant treatment for aggressive TNBC. Breast cancer is the most common cause of cancer-related death among females worldwide (1). Between 15~20% of breast cancer patients are diagnosed with triple-negative breast cancer (TNBC) based on the absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) (2). Unlike other types of breast cancer, TNBC has a poor prognosis with first-line chemotherapy such as anthracyclines and taxanes, and does not have additional treatment options, such as hormonal treatments or targeted therapy, following conventional first-line adjuvant chemotherapy. For this reason, novel therapeutics for TNBC are required, but this is still challenging. Methionine addiction is a fundamental and general hallmark of cancer (3). Methionine addiction, discovered by our laboratory, involves elevated methionine flux in cancer cells (4-6) due to elevated transmethylation-reactions (5, 7). Methionine overuse by cancer cells is known as the Hoffman effect, analogous to the Warburg effect of glucose overuse by cancer cells (8). Methionine restriction results in free-methionine and S-adenosylmethionine (SAM) depletion (6, 7, 9), and selective cell-cycle arrest in the S/G 2 phase in cancer cells (10, 11). Methionine addiction and DNA hypomethylation in human cancer, also discovered in our laboratory (12), are related (13, 14). Because methionine addiction is tightly linked to other features of cancer (15) and is a general phenomenon of cancer, it can be an important target for cancer treatment. Recently, Jeon et al. (16) observed that methionine restriction with a lowmethionine diet inhibited TNBC metastasis in mouse models. Recombinant methioninase (rMETase), a purified methioninecleaving enzyme, can target methionine addiction and can be used to treat any cancer by methionine restriction which selectively traps the cells in the S/G 2-phase of the cell cycle, where they are susceptible to most cytotoxic chemotherapy and can be successfully eradicated (17, 18). METase already ...

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Oral Recombinant Methioninase, Combined With Oral Caffeine and Injected Cisplatinum, Overcome Cisplatinum-Resistance and Regresses Patient-derived Orthotopic Xenograft Model of Osteosarcoma

Cited by 30 publications

References 14 publications

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

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

PPARγ Agonist Pioglitazone in Combination With Cisplatinum Arrests a Chemotherapy-resistant Osteosarcoma PDOX Model

Oral Methioninase Inhibits Recurrence in a PDOX Mouse Model of Aggressive Triple-negative Breast Cancer

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