Su Su Thae Hnit1, Mu Yao1, Chanlu Xie1, Guangbo Ge2, Ling Bi3, Shenyi Jin3, Lijing Jiao3, Ling Xu3, Lina Long4, Hong Nie4, Yu Jin5, Linda Rogers6, Natalka Suchowerska6, Matthew Wong7, Tao Liu7, Paul De Souza8, Zhong Li9, Qihan Dong10. 1. Chinese Medicine Anti-Cancer Evaluation Program, Greg Brown Laboratory, Central Clinical School and Charles Perkins Centre, The University of Sydney, Sydney, Australia; Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia. 2. Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China. 3. Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China. 4. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China. 5. School of Pharmacy, East China University of Science and Technology, China. 6. VectorLAB, Department of Radiation Oncology, Chris O'Brien Lifehouse, Sydney, Australia; School of Physics, The University of Sydney, Sydney, Australia. 7. Children's Cancer Institute Australia for Medical Research, Sydney, NSW, Australia; Centre for Childhood Cancer Research, UNSW Medicine, Sydney, Australia. 8. School of Medicine, Western Sydney University, Australia. 9. Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China. Electronic address: lizhong@bucm.edu.cn. 10. Chinese Medicine Anti-Cancer Evaluation Program, Greg Brown Laboratory, Central Clinical School and Charles Perkins Centre, The University of Sydney, Sydney, Australia; Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia; School of Science and Health, Western Sydney University, Australia. Electronic address: qihan.dong@sydney.edu.au.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Hedyotis diffusa Willd. (H) and Scutellaria barbata D.Don (S) are ancient anti-cancer Chinese herb medicines. When combined, known as HS, it is one of the most commonly prescribed Chinese Medicines for cancer patients today in China. AIM OF THE STUDY: The prevention of disease progression is a dominant concern for the growing number of men with prostate cancer. The purpose of this work is to evaluate the action and mode of action of Chinese Medicine recipe HS in inhibiting prostate cancer progression in preclinical models. METHODS: Effects of HS were analyzed in prostate cancer cell lines by evaluating proliferation, cell cycle profile, DNA damage and key regulators responsible for G2 to M phase transition. The transcriptional activities of these regulators were determined by RT-PCR and ChIP. The efficacy of HS in vitro was validated in an animal model. RESULTS: HS treatment was observed to reduce DNA content and accumulated prostate cancer cells at the G2/M phase. Immunolabeling for phospho-Histone H3 in association with nocodazole to capture mitotic cells confirmed that HS impeded G2 to M transition. After excluding DNA damage-induced G2 arrest, it was revealed that HS reduced expression of Cyclin B1, CDK1, PLK1 and Aurora A at both protein and mRNA levels, with concomitant reduction of H3K4 tri-methylation at their promoter-regions. Animals that received oral administration of HS with a dosage relevant to clinical application showed reduced tumor volume and weight with a reduction of Cyclin B1, CDK1, PLK1 and Aurora A protein levels. CONCLUSIONS: HS acts by impeding the G2 to M transition of prostate cancer cells. It is likely that the mode of action is transcriptionally suppressing proteins governing mitotic entry, without eliciting significant DNA damage.
ETHNOPHARMACOLOGICAL RELEVANCE: Hedyotis diffusa Willd. (H) and Scutellaria barbata D.Don (S) are ancient anti-cancer Chinese herb medicines. When combined, known as HS, it is one of the most commonly prescribed Chinese Medicines for cancerpatients today in China. AIM OF THE STUDY: The prevention of disease progression is a dominant concern for the growing number of men with prostate cancer. The purpose of this work is to evaluate the action and mode of action of Chinese Medicine recipe HS in inhibiting prostate cancer progression in preclinical models. METHODS: Effects of HS were analyzed in prostate cancer cell lines by evaluating proliferation, cell cycle profile, DNA damage and key regulators responsible for G2 to M phase transition. The transcriptional activities of these regulators were determined by RT-PCR and ChIP. The efficacy of HS in vitro was validated in an animal model. RESULTS: HS treatment was observed to reduce DNA content and accumulated prostate cancer cells at the G2/M phase. Immunolabeling for phospho-Histone H3 in association with nocodazole to capture mitotic cells confirmed that HS impeded G2 to M transition. After excluding DNA damage-induced G2 arrest, it was revealed that HS reduced expression of Cyclin B1, CDK1, PLK1 and Aurora A at both protein and mRNA levels, with concomitant reduction of H3K4 tri-methylation at their promoter-regions. Animals that received oral administration of HS with a dosage relevant to clinical application showed reduced tumor volume and weight with a reduction of Cyclin B1, CDK1, PLK1 and Aurora A protein levels. CONCLUSIONS: HS acts by impeding the G2 to M transition of prostate cancer cells. It is likely that the mode of action is transcriptionally suppressing proteins governing mitotic entry, without eliciting significant DNA damage.
Authors: Su Su Thae Hnit; Mu Yao; Chanlu Xie; Ling Bi; Matthew Wong; Tao Liu; Paul De Souza; Zhong Li; Qihan Dong Journal: Discov Oncol Date: 2022-06-07