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Anti-Cancer Agents from Natural Sources
Published in Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg, Promising Drug Molecules of Natural Origin, 2020
Debasish Bandyopadhyay, Felipe Gonzalez
Arginase is a manganese-containing enzyme that is part of the ureohydrolase family. It carries out the role of a catalyst in the final step of the urea cycle, which transforms L-arginine into L-ornithine and urea. This might be the reason of the anticancer potential of L-arginase. Normal cells remain unaffected when Arginase converts L-arginine to ornithine because normal cells synthesize citrulline from ornithine but Cancerous cells are unable to do that. Studies showed that pegylated arginine deiminase (ADI-PEG2), a known anticancer enzyme that reduces arginine, can initiate cancerous cell death. Takaku et al. (1992, 1995) demonstrated that ADI could cause cell damage and ultimately death in HCC (hepatocellular carcinoma) and in deadly skin cancer, melanoma. In vitro MH134 liver cancer and Meth A fibrosarcoma cells lines were inhibited by 20 ng/ml of ADI. The reticence of cellular growth was due to lessening in L-arginine. ADI-PEG20 was tested in human trials on a single patient diagnosed with HCC (Curley et al., 2003). The study revealed that ADI-PEG20 could promote cellular death without directly effecting normal healthy cells. The optimal dose, which was the one that reduced tumor size was 160 IU/m2. This concluded that ADI-PEG20 might have antitumor activity with low-toxicity with higher potency. Subsequently, new investigations were conducted to achieve a bigger view on the mechanistic action ofADIPEG20. In a recent phase II trial (Tsai et al., 2013), on AML patients, treated with ADI-PEG20 was reported. The study involved 43 patients. Out of 43 patients, 22 passed away due to disease. Two patients showed complete response (CR) to ADI-PEG20. The studies conducted on both of those patients suggested that arginosuccinate synthetase played crucial part in developing malignancy. Additionally, some AML makers and c-MYC regulated genes were imperative factors to determine the response to ADI-PEG20.
Intestinal luminal putrescine is produced by collective biosynthetic pathways of the commensal microbiome
Published in Gut Microbes, 2019
Atsuo Nakamura, Takushi Ooga, Mitsuharu Matsumoto
Alternatively, putrescine may be synthesised via agmatine, which is generated from arginine by arginine decarboxylase. In fact, the dominant species that colonise the human intestine have arginine decarboxylase,29 which catalyses the conversion of arginine to agmatine and CO2. Subsequently, agmatine may then be converted directly into putrescine and urea by agmatine ureohydrolase, or indirectly to N-carbamoylputrescine, through agmatine deiminase and subsequently into putrescine by putrescine carbamoyltransferase or n-carbamoyl putrescine amidase. We found that species that take up extracellular agmatine and subsequently release putrescine must also be present in the intestinal microbiome, as putrescine was significantly increased in faecal cultures supplemented with agmatine. In contrast, agmatine did not accumulate in faecal cultures supplemented with arginine. Additionally, isotope-labelled agmatine was detected in colonic contents from only one of three rats treated with isotope-labelled arginine, suggesting that agmatine in the extracellular space was rapidly utilised or released only in small amounts.