Natural polyphenols facilitate elimination of HT-29 colorectal cancer xenografts by chemoradiotherapy: a Bcl-2- and superoxide dismutase 2-dependent mechanism.

Abstract

Colorectal cancer is one of the most common malignancies worldwide. The treatment of advanced colorectal cancer with chemotherapy and radiation has two major problems: development of tumor resistance to therapy and nonspecific toxicity towards normal tissues. Different plant-derived polyphenols show anticancer properties and are pharmacologically safe. In vitro growth of human HT-29 colorectal cancer cells is inhibited ( approximately 56%) by bioavailable concentrations of trans-pterostilbene (trans-3,5-dimethoxy-4'-hydroxystilbene; t-PTER) and quercetin (3,3',4',5,6-pentahydroxyflavone; QUER), two structurally related and naturally occurring small polyphenols. I.v. administration of t-PTER and QUER (20 mg/kg x day) inhibits growth of HT-29 xenografts ( approximately 51%). Combined administration of t-PTER + QUER, FOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil; a first-line chemotherapy regimen), and radiotherapy (X-rays) eliminates HT-29 cells growing in vivo leading to long-term survival (>120 days). Gene expression analysis of a Bcl-2 family of genes and antioxidant enzymes revealed that t-PTER + QUER treatment preferentially promotes, in HT-29 cells growing in vivo, (a) superoxide dismutase 2 overexpression ( approximately 5.7-fold, via specificity protein 1-dependent transcription regulation) and (b) down-regulation of bcl-2 expression ( approximately 3.3-fold, via inhibition of nuclear factor-kappaB activation). Antisense oligodeoxynucleotides to human superoxide dismutase 2 and/or ectopic bcl-2 overexpression avoided polyphenols and chemoradiotherapy-induced colorectal cancer elimination and showed that the mangano-type superoxide dismutase and Bcl-2 are key targets in the molecular mechanism activated by the combined application of t-PTER and QUER.

• Authors: Sonia Priego, Fatima Feddi, Paula Ferrer, Salvador Mena, María Benlloch, Angel Ortega, Julian Carretero, Elena Obrador, Miguel Asensi, José M Estrela
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 10 Pg. 3330-42 (Oct 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18852136 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Antioxidants
• Flavonoids
• NF-kappa B
• Phenols
• Polyphenols
• Proto-Oncogene Proteins c-bcl-2
• Sp1 Transcription Factor
• Superoxide Dismutase
• superoxide dismutase 2

Topics

• Animals
• Antineoplastic Agents (therapeutic use, toxicity)
• Antioxidants (metabolism)
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, enzymology, genetics, radiotherapy)
• Down-Regulation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Flavonoids (pharmacology, therapeutic use, toxicity)
• Gene Expression Profiling
• HT29 Cells
• Humans
• Mice
• Mice, Nude
• NF-kappa B (metabolism)
• Phenols (pharmacology, therapeutic use, toxicity)
• Polyphenols
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Sp1 Transcription Factor (metabolism)
• Superoxide Dismutase (metabolism)
• Up-Regulation (drug effects)
• Xenograft Model Antitumor Assays