theanine and Neoplasms

A growing literature indicates several health benefits of theanine, a major nonprotein derivative amino acid special to tea, and a nonedible mushroom. This study aimed to systematically review the scientific evidence regarding the anticarcinogen and anticancer effects of natural theanine. A systematic search for the relevant articles published until January 2021 on MEDLINE, Scopus, and Web of Knowledge was conducted. Out of 377 initial records, 14 in vitro, ex vivo, and in vivo studies met our inclusion criteria. Most of the included in vitro and ex vivo studies reported beneficial effects of theanine on the proliferation, apoptosis, metastasis, migration, and invasion in various cancer cell lines. The in vivo studies also supported the potential impacts of theanine on cancer incidence or progression. Theanine exerted its anticancer function by inhibiting EGFR, VEGFR, Met, and Akt/mTOR, JAK2/STAT3, and ERK/NFκB pathways, as well as activating the intrinsic apoptosis pathway and caspase-independent programmed cell death. In conclusion, the results indicated moderate apoptotic, antimetastatic, antimigration, and anti-invasion effects, along with the mild antiproliferative influence of theanine on cancer. Further studies are necessary to ascertain the effectiveness of theanine on the prevention and suppression of cancer and shed light upon the attributable mechanisms in the in vivo condition.

Topics: Glutamates; Humans; Neoplasms; Signal Transduction; Tea

Tea has been a very popular beverage around the world for centuries. The reason that it is delicious, enabling hydration, showing warming and relaxing effect can be mentioned why it is consumed so much in addition to its prominent health effects. Although the catechins and caffeine are the primary bioactive components that are related with the health effects of the tea, the health effects of theanine amino acid, which is a nonproteinic amino acid special to tea, has become prominent in recent years. It has been known that the theanine amino acid in tea has positive effects especially on relaxing, cognitive performance, emotional status, sleep quality, cancer, cardiovascular diseases, obesity, and common cold. The results of acute and chronic toxicity tests conducted on the safety of theanine express that L-theanine is reliable in general even if it is consumed too much with diet. However, it has not revealed a clear evidence-based result yet regarding theanine metabolism, health effects, and its safety. Within this frame, chemical structure of theanine, its biosynthesis, dietary sources, metabolism, health effects, and safety are discussed in present study.

Topics: Cardiovascular Diseases; Cognition; Glutamates; Humans; Neoplasms; Obesity; Plant Leaves; Randomized Controlled Trials as Topic; Sleep; Stress, Physiological; Tea

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

Biochemical modulation has played an important role in the development of cancer chemotherapy. The combined effects of theanine, a specific amino acid in green tea, and glutamate transporter inhibitors on the antitumor activity of doxorubicin (DOX), were investigated and we clarified the biochemical mechanisms of action of these modulators. In M5076 ovarian sarcoma-bearing mice, theanine significantly enhanced the inhibitory effect of DOX on tumor growth and increased the DOX concentration in the tumor, compared to DOX-alone group. Furthermore, the oral administration of theanine or green tea similarly enhanced the antitumor activity of DOX. Moreover, the combination of theanine with DOX suppressed the hepatic metastasis of ovarian sarcoma. In contrast, an increase in DOX concentration was not observed in normal tissues, such as liver and heart. Namely, theanine did not enhance, rather it tended to normalize the increase of lipid peroxide (LPO) levels and reduction of glutathione peroxidase activity as indicators of the DOX-induced side toxicity. On the other hand, in vitro experiments proved that theanine inhibited the efflux of DOX from tumor cells, supporting a theanine-induced increase in the DOX concentration in tumors in vivo. Moreover, theanine significantly inhibited the glutamate uptake by M5076 cells similar to specific inhibitors. Two astrocytic high-affinity glutamate transporters, GLAST and GLT-1, were expressed in M5076 cells. These results suggested that the inhibition of DOX efflux was induced by theanine-mediated inhibition of glutamate transporters. The reduction in the concentration of glutamate in tumor cells caused by theanine induced decreases in the intracellular glutathione (GSH) and GS-DOX conjugate levels. As the expression of MRP5 in M5076 cells was confirmed, it is suggested that the GS-DOX conjugate was transported extracellularly via the MRP5/GS-X pump in M5076 cells and that theanine affected this route. Namely, theanine increases the concentration of DOX in a tumor in vivo through inhibition of the glutamate transporter via the GS-X pump. Similarly, dihydrokainate (DHK) and L-serine-O-sulfate (SOS), specific glutamate transporter inhibitors, indicated the enhancement of the DOX antitumor activity via inhibition of glutamate uptake. Therefore, we revealed the novel mechanism of enhancement of antitumor efficacy of DOX via the inhibition of glutamate transporters. Similarly, theanine enhanced the antitumor activities of other

Topics: Amino Acid Transport System X-AG; Animals; Antineoplastic Agents; Doxorubicin; Drug Synergism; Enzyme Inhibitors; Glutamates; Humans; Mice; Neoplasms

Cachexia is a common cancer complication and is associated with weight loss and anorexia. In this study, we investigated the ameliorating effects of cystine and theanine on cancer cachexia using a mouse model. In mice carrying the colon cancer cell line C-26, there was a suppression of body weight increase and reduction in both internal fat and lower limb muscles. Repeated cystine and theanine administration significantly prevented weight loss, internal fat loss, lower limb muscle loss, and serum IL-6 increase in the cachexia model. These results suggested that cystine and theanine may be effective in ameliorating cancer cachexia.

Topics: Cachexia; Cystine; Humans; Neoplasms; Weight Loss

Cystine and theanine (CT), an amino acid mixture, provides the substrates cysteine and glutamic acid that promote glutathione synthesis. We previously reported that CT pre-treatment significantly improved the acute survival rate and reduced acute radiation injury of the small intestine and bone marrow of rats after 5 Gy of total body X-ray irradiation. To examine the long-term effects of CT administration after irradiation, we investigated the effects of CT pre-treatment and pre- and post-treatment on the chronic survival rate and solid tumor (spleen, skin and subcutis, and thyroid) incidence after irradiation using 7-week-old male Wistar rats. CT pre-treatment of 280 mg/kg was administered orally for 5 days before 5 Gy irradiation, and CT pre- and post-treatment was administered 5 days before and 5 days after irradiation. A 0.5% carboxymethyl cellulose solution was administered as a control. The chronic survival rate of the pre-treated rats was higher than that of the control rats at 441 days after irradiation (40 vs 8.1%, P = 0.011). However, the survival rate did not significantly differ between the pre- and post-treatment and control rats at 467 days after irradiation (33.8 vs 30.2%, P = 0.792). In addition, more solid tumors, especially subcutis sarcomas, were observed in the pre-treatment rats (26.1%, 6/23) than in the control rats (4.5%, 1/22) after irradiation. Therefore, pre-administration of CT improves the chronic survival rate after irradiation; however, the occurrence of solid tumors was not suppressed.

Topics: Animals; Cystine; Glutathione; Incidence; Male; Neoplasms; Rats; Rats, Wistar; Survival Rate; Whole-Body Irradiation; X-Rays

Oxaliplatin frequently causes severe peripheral neuropathy as a dose-limiting toxicity. However, this toxicity lacks a strategy for prevention. Cystine/Theanine is a supplement, which includes precursors for the biosynthesis of glutathione. In this study, we investigated the effects of Cystine/Theanine on oxaliplatin-induced peripheral neuropathy using an in vivo model. Repeated injection of oxaliplatin (4 mg/kg intraperitoneally twice a week for 2 weeks) caused mechanical allodynia, cold hyperalgesia and axonal degeneration of the sciatic nerve in rats. Mechanical allodynia and axonal degeneration, but not cold hyperalgesia, were ameliorated by daily co-administration of Cystine [200 mg/kg orally (p.o.)] and Theanine (80 mg/kg p.o.). Moreover, co-administration of Cystine and Theanine to rats significantly increased the glutathione level in the sciatic nerve compared with the oxaliplatin group. Furthermore, Cystine and Theanine did not attenuate the tumour cytotoxicity of oxaliplatin in C-26 tumour cell-bearing mice. These findings suggest that Cystine and Theanine may be beneficial for preventing oxaliplatin-induced peripheral neuropathy.

Topics: Administration, Oral; Animals; Cold Temperature; Cystine; Disease Models, Animal; Drug Therapy, Combination; Glutamates; Glutathione; Hyperalgesia; Male; Mice; Neoplasms; Oxaliplatin; PC12 Cells; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Sciatic Nerve

Theanine, an active component of green tea (Camellia sinensis), is considered a modulator of chemotherapy. To further investigate the anticancer activity of theanine, the present study investigated the cytotoxic effect of theanine at the concentration of 600 µg/ml, in the human HepG2 hepatoblastoma and HeLa adenocarcinoma cell lines, in comparison with the normal L02, H9c2 and HEK293 cell lines using a MTT assay. It was found that theanine induced cell death in the tumor cells, but not in the normal cells. Notably, when glutamine was restricted or reduced in the cell culture medium, the cell death induced by theanine was significantly enhanced. A terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling assay indicated that DNA damage was induced in theanine‑treated HepG2 cells. Further experiments demonstrated that theanine caused HepG2 cell apoptosis through the mitochondrial pathway, with a loss of membrane potential and the release of apoptosis‑inducing factor, endonuclease G and cytochrome c. Western blot analysis and caspase activity detection also revealed that caspase‑9 and caspase‑3 were activated, whereas caspase‑8 remained inactive. These observations suggested that theanine exerted potent cytotoxicity on tumor cells when glutamine was restricted.

Topics: Apoptosis; Caspase 3; Caspase 8; Cell Proliferation; Cytochromes c; DNA Damage; Gene Expression Regulation, Neoplastic; Glutamates; Glutamine; HEK293 Cells; HeLa Cells; Hep G2 Cells; Humans; Membrane Potential, Mitochondrial; Mitochondria; Neoplasms; Signal Transduction; Tea