Natural polyphenols facilitate elimination of HT-29 colorectal cancer xenografts by chemoradiotherapy: a Bcl-2- and superoxide dismutase 2-dependent mechanism.
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.
Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 17 Av. Blasco Ibañez, 46010 Valencia, Spain.
Sonia
S
Priego
Fatima
F
Feddi
Paula
P
Ferrer
Salvador
S
Mena
María
M
Benlloch
Angel
A
Ortega
Julian
J
Carretero
Elena
E
Obrador
Miguel
M
Asensi
José M
JM
Estrela
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D000975:Antioxidants / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000532:radiotherapy*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D020869:Gene Expression Profiling; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D059808:Polyphenols; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099156:Superoxide Dismutase 2
D000970:Antineoplastic Agents; D000975:Antioxidants; D005419:Flavonoids; D016328:NF-kappa B; D010636:Phenols; D059808:Polyphenols; D019253:Proto-Oncogene Proteins c-bcl-2; D016329:Sp1 Transcription Factor; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2