A bioengineered arginine-depleting enzyme as a long-lasting therapeutic agent against cancer

Chung, Sai Fung; Kim, Chi Fai; Tam, Suet Ying; Choi, Man Chung; So, Pui‐Kin; Wong, Kwok Yin; Leung, Yun Chung; Lo, Wai Hung

doi:10.1007/s00253-020-10484-4

Cited by 14 publications

(6 citation statements)

References 41 publications

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“…Thus, it is urgent to develop a safe and promising alternative way to treat GC. Arginine depletion therapy is a relatively new, safe, and promising anti-cancer strategy for treating various cancer cell lines such as lung [9,31], liver [8,32], laryngeal [33] and colorectal cancers [6]. The PEGylated form of ADI (ADI-PEG20) has shown satisfactory therapeutic results in treating liver cancer and melanoma and has been applied in clinical trials [22,24], but its therapeutic efficacy is associated with the expression of ASS, it becomes ineffective when the cancer cells are ASS-positive or when the expression of ASS gene is up-regulated during the ADI-PEG20 treatment.…”

Section: Discussionmentioning

confidence: 99%

Mono-PEGylated thermostable Bacillus caldovelox arginase mutant (BCA-M-PEG20) induces apoptosis, autophagy, cell cycle arrest and growth inhibition in gastric cancer cells

et al. 2022

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Gastric cancer is one of the most common malignant solid tumors in the world, especially in Asia with high mortality due to a lack of effective treatment. The potential usage of the newly constructed arginine-depleting enzyme—mono-PEGylated Bacillus caldovelox arginase mutant (BCA-M-PEG20), an effective drug against multiple cancer cell lines such as cervical and lung cancers, for the treatment of gastric cancer was demonstrated. Our results indicated that BCA-M-PEG20 significantly inhibited argininosuccinate synthetase (ASS)-positive gastric cancer cells, MKN-45 and BGC-823, while another arginine-depleting enzyme, arginine deiminase (ADI, currently under Phase III clinical trial), failed to suppress the growth of gastric cancer cells. In vitro studies demonstrated that BCA-M-PEG20 inhibited MKN-45 cells by inducing autophagy and cell cycle arrest at the S phase under 0.58 U/mL (IC50 values). Significant caspase-dependent apoptosis was induced in MKN-45 after the treatment with 2.32 U/mL of BCA-M-PEG20. In vivo studies showed that administrations of BCA-M-PEG20 at 250 U/mouse twice per week significantly suppressed about 50% of tumor growth in the MKN-45 gastric cancer xenograft model. Taken together, BCA-M-PEG20 demonstrated a superior potential to be an anti-gastric cancer drug.

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Section: Discussionmentioning

confidence: 99%

Mono-PEGylated thermostable Bacillus caldovelox arginase mutant (BCA-M-PEG20) induces apoptosis, autophagy, cell cycle arrest and growth inhibition in gastric cancer cells

et al. 2022

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“…The mono-PEGylation strategy ensures drug homogeneity and assures the quality of the drug [ 36 , 37 , 38 , 39 , 40 ]. BCA-M was genetically modified to replace a serine with a cysteine residue (Ser 161 → Cys 161 ) that would subsequently be used for the coupling of a 20 kDa PEG-maleimide.…”

Section: Discussionmentioning

confidence: 99%

Mono-PEGylation of a Thermostable Arginine-Depleting Enzyme for the Treatment of Lung Cancer

Chung

Kim

Kwok

et al. 2020

IJMS

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L-arginine (L-Arg) depletion induced by randomly PEGylated arginine deiminase (ADI-PEG20) can treat arginosuccinate synthase (ASS)-negative cancers, and ADI-PEG20 is undergoing phase III clinical trials. Unfortunately, ASS-positive cancers are resistant to ADI-PEG20. Moreover, the yield of ADI production is low because of the formation of inclusion bodies. Here, we report a thermostable arginine-depleting enzyme, Bacillus caldovelox arginase mutant (BCA-M: Ser161->Cys161). An abundant amount of BCA-M was easily obtained via high cell-density fermentation and heat treatment purification. Subsequently, we prepared BCA-M-PEG20, by conjugating a single 20 kDa PEG monomer onto the Cys161 residue via thio-chemistry. Unlike ADI-PEG20, BCA-M-PEG20 significantly inhibited ASS-positive lung cancer cell growth. Pharmacodynamic studies showed that a single intraperitoneal injection (i.p). administration of 250 U/mouse of BCA-M-PEG20 induced low L-Arg level over 168 h. The mono-PEGylation of BCA-M prolonged its elimination half-life from 6.4 to 91.4 h (a 14-fold increase). In an A549 lung cancer xenograft model, a weekly administration of 250 U/mouse of BCA-M-PEG20 suppressed tumor growth significantly. We also observed that BCA-M-PEG20 did not cause any significant safety issue in mouse models. Overall, BCA-M-PEG20 showed excellent results in drug production, potency, and stability. Thereby, it has great potential to become a promising candidate for lung cancer therapy.

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“…Human arginase 1 mutant-PEG 20 (HAI-PEG 20) is a mono-PEGylated rhArg1 that effectively inhibits the growth of at least eight types of cancer cells in vitro and in vivo [ 149 ]. To produce this drug, researchers screened metal ions to create a site-specific mono-PEGylated human arginase I mutant conjugated to PEG-maleimide to produce a homogeneous product.…”

Section: Enzyme-mediated Arginine Deprivation Agents For Cancer Thera...mentioning

confidence: 99%

“…Both Co-HAI-PEG20L and Ni-HAI-PEG20L inhibited the growth of eight types of cancer cell lines in vitro, and in mice, and maintained L-arginine levels below the detection limit for over 120 h without significant toxicity. While these findings suggest the potential of Co-HAI-PEG20L and Ni-HAI-PEG20L for anticancer therapy, their efficacy needs further evaluation in clinical trials [ 149 ].…”

Section: Enzyme-mediated Arginine Deprivation Agents For Cancer Thera...mentioning

confidence: 99%

Unlocking the Potential of Arginine Deprivation Therapy: Recent Breakthroughs and Promising Future for Cancer Treatment

Chu

Lai

Yeh

2023

IJMS

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Arginine is a semi-essential amino acid that supports protein synthesis to maintain cellular functions. Recent studies suggest that arginine also promotes wound healing, cell division, ammonia metabolism, immune system regulation, and hormone biosynthesis—all of which are critical for tumor growth. These discoveries, coupled with the understanding of cancer cell metabolic reprogramming, have led to renewed interest in arginine deprivation as a new anticancer therapy. Several arginine deprivation strategies have been developed and entered clinical trials. The main principle behind these therapies is that arginine auxotrophic tumors rely on external arginine sources for growth because they carry reduced key arginine-synthesizing enzymes such as argininosuccinate synthase 1 (ASS1) in the intracellular arginine cycle. To obtain anticancer effects, modified arginine-degrading enzymes, such as PEGylated recombinant human arginase 1 (rhArg1-PEG) and arginine deiminase (ADI-PEG 20), have been developed and shown to be safe and effective in clinical trials. They have been tried as a monotherapy or in combination with other existing therapies. This review discusses recent advances in arginine deprivation therapy, including the molecular basis of extracellular arginine degradation leading to tumor cell death, and how this approach could be a valuable addition to the current anticancer arsenal.

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A bioengineered arginine-depleting enzyme as a long-lasting therapeutic agent against cancer

Cited by 14 publications

References 41 publications

Mono-PEGylated thermostable Bacillus caldovelox arginase mutant (BCA-M-PEG20) induces apoptosis, autophagy, cell cycle arrest and growth inhibition in gastric cancer cells

Mono-PEGylated thermostable Bacillus caldovelox arginase mutant (BCA-M-PEG20) induces apoptosis, autophagy, cell cycle arrest and growth inhibition in gastric cancer cells

Mono-PEGylation of a Thermostable Arginine-Depleting Enzyme for the Treatment of Lung Cancer

Unlocking the Potential of Arginine Deprivation Therapy: Recent Breakthroughs and Promising Future for Cancer Treatment

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