title: The traditional Chinese medical compound Rocaglamide protects nonmalignant primary cells from DNA damage-induced toxicity by inhibition of p53 expression.
abstract: One of the main obstacles of conventional anticancer therapy is the toxicity of chemotherapeutics to normal tissues. So far, clinical approaches that aim to specifically reduce chemotherapy-mediated toxicities are rare. Recently, a number of studies have demonstrated that herbal extracts derived from traditional Chinese medicine (TCM) may reduce chemotherapy-induced side effects. Thus, we screened a panel of published cancer-inhibiting TCM compounds for their chemoprotective potential and identified the phytochemical Rocaglamide (Roc-A) as a candidate. We show that Roc-A significantly reduces apoptotic cell death induced by DNA-damaging anticancer drugs in primary human and murine cells. Investigation of the molecular mechanism of Roc-A-mediated protection revealed that Roc-A specifically blocks DNA damage-induced upregulation of the transcription factor p53 by inhibiting its protein synthesis. The essential role of p53 in Roc-A-mediated protection was confirmed by siRNA knockdown of p53 and by comparison of the effects of Roc-A on chemoprotection of splenocytes isolated from wild-type and p53-deficient mice. Importantly, Roc-A did not protect p53-deficient or -mutated cancer cells. Our data suggest that Roc-A may be used as an adjuvant to reduce the side effects of chemotherapy in patients with p53-deficient or -mutated tumors.
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), INF-280, D-69120 Heidelberg, Germany.
authors.forename: M S
authors.initials: MS
authors.lastname: Becker
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Centre (DKFZ), INF-280, D-69120 Heidelberg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Schmezer
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), INF-280, D-69120 Heidelberg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Breuer
authors.affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: S F
authors.initials: SF
authors.lastname: Haas
authors.affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M A
authors.initials: MA
authors.lastname: Essers
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), INF-280, D-69120 Heidelberg, Germany.
authors.forename: P H
authors.initials: PH
authors.lastname: Krammer
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), INF-280, D-69120 Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Li-Weber
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D020011:Protective Agents / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; D004365:Drugs, Chinese Herbal; D020011:Protective Agents; D016159:Tumor Suppressor Protein p53; C107772:rocaglamide