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.
Highlights
Roc-A-mediated protection revealed that Roc-A blocks DNA damage-induced upregulation of the transcription factor p53 by inhibiting its protein synthesis
Cell death was determined by DNA fragmentation
Cell death was determined by DNA fragmentation for Teniposide and Bleomycin treatment or by forward scatter/side scatter (FSC/SSC) profile for Doxorubicin treatment
Summary
Roc-A-mediated protection revealed that Roc-A blocks DNA damage-induced upregulation of the transcription factor p53 by inhibiting its protein synthesis. The herbal mixture PHY906, which is based on the TCM Huang Qin Tang, reduced CPT-11-induced toxicity in mice,[10] a finding that is further supported by a phase 1/2 clinical trial.[11] Other clinical studies suggest that Chinese herbal extracts may reduce the chemotherapy-induced decrease in white blood cell counts.[12] These results prompted us to investigate TCM compounds that could protect normal tissues from DNA damage-induced cell death
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