Combinatorial treatment with natural compounds in prostate cancer inhibits prostate tumor growth and leads to key modulations of cancer cell metabolism

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Abstract

High-throughput screening of a natural compound library was performed to identify the most efficacious combinatorial treatment on prostate cancer. Ursolic acid, curcumin and resveratrol were selected for further analyses and administered in vivo via the diet, either alone or in combination, in a mouse allograft model of prostate cancer. All possible combinations of these natural compounds produced synergistic effects on tumor size and weight, as predicted in the screens. A subsequent untargeted metabolomics and metabolic flux analysis using isotopically labeled glutamine indicated that the compound combinations modulated glutamine metabolism. In addition, ASCT2 levels and STAT3, mTORC1 and AMPK activity were modulated to a greater extent by the combinations compared to the individual compounds. Overall, this approach can be useful for identifying synergistic combinations of natural compounds for chemopreventive and therapeutic interventions.

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Most cited references 53

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Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.

Arun Sreekumar, Laila Poisson, Thekkelnaycke M Rajendiran … (2009)

Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer and metastatic disease. Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly increased during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells. Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity.

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Cancer chemoprevention with dietary phytochemicals.

Young-Joon Surh (2003)

Chemoprevention refers to the use of agents to inhibit, reverse or retard tumorigenesis. Numerous phytochemicals derived from edible plants have been reported to interfere with a specific stage of the carcinogenic process. Many mechanisms have been shown to account for the anticarcinogenic actions of dietary constituents, but attention has recently been focused on intracellular-signalling cascades as common molecular targets for various chemopreventive phytochemicals.

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Curcumin: the story so far.

R A Sharma, A Gescher, W Steward (2005)

Curcumin is a polyphenol derived from the herbal remedy and dietary spice turmeric. It possesses diverse anti-inflammatory and anti-cancer properties following oral or topical administration. Apart from curcumin's potent antioxidant capacity at neutral and acidic pH, its mechanisms of action include inhibition of several cell signalling pathways at multiple levels, effects on cellular enzymes such as cyclooxygenase and glutathione S-transferases, immuno-modulation and effects on angiogenesis and cell-cell adhesion. Curcumin's ability to affect gene transcription and to induce apoptosis in preclinical models is likely to be of particular relevance to cancer chemoprevention and chemotherapy in patients. Although curcumin's low systemic bioavailability following oral dosing may limit access of sufficient concentrations for pharmacological effect in certain tissues, the attainment of biologically active levels in the gastrointestinal tract has been demonstrated in animals and humans. Sufficient data currently exist to advocate phase II clinical evaluation of oral curcumin in patients with invasive malignancy or pre-invasive lesions of the gastrointestinal tract, particularly the colon and rectum.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101708166

Journal ID (pubmed-jr-id): 46711

Journal ID (nlm-ta): NPJ Precis Oncol

Journal ID (iso-abbrev): NPJ Precis Oncol

Title: NPJ precision oncology

ISSN (Electronic): 2397-768X

Publication date Nihms-submitted: 12 July 2017

Publication date (Electronic): 5 June 2017

Publication date (Print): 2017

Publication date PMC-release: 28 November 2017

Volume: 1

Electronic Location Identifier: 18

Affiliations

[1 ]Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, USA

[2 ]Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA

[3 ]Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX, USA

[4 ]The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA

Author notes

Correspondence: Stefano Tiziani ( tiziani@ 123456austin.utexas.edu )

Alessia Lodi and Achinto Saha contributed equally to this work

Article

Manuscript ID: NIHMS889941

DOI: 10.1038/s41698-017-0024-z

PMC ID: 5705091

PubMed ID: 29873330

SO-VID: 09461b79-272f-4135-8a1f-657ebbb8b38b

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Combinatorial treatment with natural compounds in prostate cancer inhibits prostate tumor growth and leads to key modulations of cancer cell metabolism

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Cancer Metabolism

Most cited references 53

Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.

Cancer chemoprevention with dietary phytochemicals.

Curcumin: the story so far.

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