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

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Summary

Introduction

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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