Curcumin (diferuloylmethane) is a polyphenol derived from the plant Curcuma longa, commonly called turmeric. Extensive research over the last 50 years has indicated this polyphenol can both prevent and treat cancer. The anticancer potential of curcumin stems from its ability to suppress proliferation of a wide variety of tumor cells, down-regulate transcription factors NF- κB, AP-1 and Egr-1; down-regulate the expression of COX2, LOX, NOS, MMP-9, uPA, TNF, chemokines, cell surface adhesion molecules and cyclin D1; down-regulate growth factor receptors (such as EGFR and HER2); and inhibit the activity of c-Jun N-terminal kinase, protein tyrosine kinases and protein serine/threonine kinases. In several systems, curcumin has been described as a potent antioxidant and anti-inflammatory agent. Evidence has also been presented to suggest that curcumin can suppress tumor initiation, promotion and metastasis. Pharmacologically, curcumin has been found to be safe. Human clinical trials indicated no dose-limiting toxicity when administered at doses up to 10 g/day. All of these studies suggest that curcumin has enormous potential in the prevention and therapy of cancer. The current review describes in detail the data supporting these studies. Curcumin, derived from turmeric (vernacular name: Haldi), is a rhizome of the plant Curcuma longa. The medicinal use of this plant has been documented in Ayurveda (the Indian

Anticancer potential of curcumin: preclinical and clinical studies.

Curcumin as “Curecumin”: From kitchen to clinic

https://jeffreydachmd.com/wp-content/uploads/2015/01/Molecular-targets-of-dietary-agents-prevention-cancer-aggarwal-2006.pdf

Molecular targets of dietary agents for prevention and therapy of cancer

Curcumin: The story so far

Multiple biological activities of curcumin: a short review.

BACKGROUND
Earlier work from our laboratory highlighted the therapeutic potential of curcumin (turmeric), used as a dietary ingredient and as a natural anti-inflammatory agent in India and other Southeast Asian countries. This agent was shown to decrease the proliferative potential and induce the apoptosis potential of both androgen-dependent and androgen-independent prostate cancer cells in vitro, largely by modulating the apoptosis suppressor proteins and by interfering with the growth factor receptor signaling pathways as exemplified by the EGF-receptor. To extend these observations made in vitro and to study the efficacy of this potential anti-cancer agent in vivo, the growth of LNCaP cells as heterotopically implanted tumors in nude mice was followed.

METHODS
The androgen-dependent LNCaP prostate cancer cells were grown, mixed with Matrigel and injected subcutaneously into nude mice. Experimental group received a synthetic diet containing 2% curcumin for up to 6 weeks. At the end point, sections taken from the excised tumors were evaluated for pathology, cell proliferation, apoptosis, and vascularity.

RESULTS
Curcumin causes a marked decrease in the extent of cell proliferation as measured by the BrdU incorporation assay and a significant increase in the extent of apoptosis as measured by an in situ cell death assay. Moreover, a significant decrease in the microvessel density as measured by the CD31 antigen staining was also seen.

CONCLUSIONS
Curcumin could be a potentially therapeutic anti-cancer agent, as it significantly inhibits prostate cancer growth, as exemplified by LNCaP in vivo, and has the potential to prevent the progression of this cancer to its hormone refractory state. Prostate 47:293–303, 2001. © 2001 Wiley-Liss, Inc.

Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo.

Many tumors readily convert l-glutamine to α-ketoglutarate. This conversion is almost invariably described as involving deamidation of l-glutamine to l-glutamate followed by a transaminase (or dehydrogenase) reaction. However, mammalian tissues possess another pathway for conversion of l-glutamine to α-ketoglutarate, namely the glutaminase II pathway: l-Glutamine is transaminated to α-ketoglutaramate, which is then deamidated to α-ketoglutarate by ω-amidase. Here we show that glutamine transaminase and ω-amidase specific activities are high in normal rat prostate. Immunohistochemical analyses revealed that glutamine transaminase K (GTK) and ω-amidase are present in normal and cancerous human prostate and that expression of these enzymes increases in parallel with aggressiveness of the cancer cells. Our findings suggest that the glutaminase II pathway is important in providing anaplerotic carbon to the tricarboxylic acid (TCA) cycle, closing the methionine salvage pathway, and in the provision of citrate carbon in normal and cancerous prostate. Finally, our data also suggest that selective inhibitors of GTK and/or ω-amidase may be clinically important for treatment of prostate cancer. In conclusion, the demonstration of a prominent glutaminase II pathway in prostate cancer cells and increased expression of the pathway with increasing aggressiveness of tumor cells provides a new perspective on 'glutamine addiction' in cancers.

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High Levels of Glutaminase II Pathway Enzymes in Normal and Cancerous Prostate Suggest a Role in 'Glutamine Addiction'.

Glutamine metabolism is largely controlled by two enzyme pathways: 1) Conversion of glutamine to glutamate catalyzed by glutaminases, followed by conversion of glutamate to α-ketoglutarate by a glutamate-linked aminotransferases (or by the action of glutamate dehydrogenase); and 2) conversion of glutamine to α-ketoglutaramate (KGM) catalyzed by glutamine-utilizing transaminases (aminotransferases), followed by conversion of KGM to α-ketoglutarate by the action of ω-amidase. The former pathway has been well documented and intensively studied for over 60 years, whereas only recently has research focused on the latter pathway, its importance in homeostasis and the control of anaplerotic metabolites. The glutamine transaminases are of fundamental importance 1) as repair enzymes (salvage of α-keto acids), 2) in nitrogen and sulfur homeostasis (closure of the methionine salvage pathway), 3) in 1-carbon metabolism, and 4) in metabolism of seleno amino acids. As a result of their broad substrate specificity the two principal mammalian glutamine transaminases (i.e. glutamine transaminases L and K) have also been characterized as kynurenine aminotransferases (KAT I and KAT III, respectively), responsible for the production of neuroactive kynurenate. The glutamine transaminases are also active with a variety of sulfur- and selenium-containing amino acids. Some of the products derived from the transamination of these amino acids may also be neuroactive (e.g. certain sulfur-containing cyclic ketimines) as well as chemopreventive (e.g. the α-keto acids derived from seleno amino acids). Of relevance to human health and disease, the glutamine transaminases may contribute to the bioactivation (toxification) of halogenated alkenes (and possibly other xenobiotic electrophiles), some of which are environmental contaminants. Finally, the role of the glutamine transaminases and ω-amidase in cancer biology has been little studied. However, the “glutamine addiction” of many tumors suggests that the glutamine transaminases together with ω-amidase may have a fundamental and influential role in regulating cancer progression

Bhuvaneswari Dorai

Papers

Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo.

High Levels of Glutaminase II Pathway Enzymes in Normal and Cancerous Prostate Suggest a Role in 'Glutamine Addiction'.

Role of Glutamine Transaminases in Nitrogen, Sulfur, Selenium, and 1-Carbon Metabolism

Role of glutamine transaminases in nitrogen, sulfur, selenium and 1-carbon metabolism: Glutamine transaminases in normal and cancer cells