Novel daidzein molecules exhibited anti-prostate cancer activity through nuclear receptor ERβ modulation, in vitro and in vivo studies

Abstract

Eight novel ERβ selective daidzein analogues (NCE1-8) were synthesized and their anti-cancer activity was evaluated by in vitro and in vivo methods. Cytotoxicity study, Receptor binding studies, Luciferase assay, cMYC & Cyclin D1 expression and Caspase 3, 8 & 9 activities were measured to ascertain the anticancer activity and mechanism. Uterotropic, anti-androgenic and anti-tumour activities were performed in rodents. The results revealed that NCEs produced anti-prostate cancer activity in DU145, LNCaP and PC3 cell lines and 50% more active than genistein. NCEs was significantly down-regulated cMYC & Cyclin D1 genes and elevated caspase 3 & 9 levels and did not show any difference in uterotropic, anti-androgenic activities. The tumour weight was also reduced. The NCE 1 and 2 have shown ERβ selectivity in receptor binding studies. Daidzein with methyl substitution at R or R₁ position exhibited more ERβ selectivity and could be considered as lead molecules for anti-prostate cancer activity.

Keywords:

• Deoxybenzoins
• estrogen receptor
• caspase
• anti-androgen
• receptor binding studies
• anticancer

Acknowledgement

The authors would like to thank PSG Sons' and Charities for providing all the facilities to carry out the work and DrSivaram Hariharan (Professor, Department of Pharmaceutical Chemistry, PSG College of Pharmacy) for correcting the manuscript for the English language. The authors also thank the Department of Science and Technology SERB, Government of India for funding the project work (File No. SR/SO/HS/0135/2012).

Disclosure statement

The authors report no conflict of interest.

Notes on contributors

R. Ranjithkumar, currently working as Post -doctoral fellow in Norton Thoracic institute, Dignity Health, St. Joseph hospital and medical centre, Phoenix, Arizona, US. He completed PhD in the field of Pharmacology. His research interests are towards understanding key molecular pathways that contribute to human diseases including transplantation and develop strategies for pharmacological intervention. His current goal is to understand the immune-pathogenesis of chronic rejection and the role of exosomes not only as a biomarker for early diagnosis of patients at risk for CLAD but also to determine the mechanism by which exosomes induced immune responses leading to CLAD.

K. Saravanan, obtained his PhD degree from Department of Chemistry, Annamalai University, Chidambaram. His area of interest is organic synthesis of novel compounds. He is also familiarized with stereochemical compound synthesis, drug designing of newer molecules targeting newer proteins.

B. Balaji, currently working in Pfizer, Chennai, he got his PhD degree from Anna University, Chennai. His area of interest is drug design, molecular modeling, estrogen receptor target therapeutic compounds development and related discoveries. He also works in anti fertility activity of Soy products.

S. Hima, is a Research Fellow at Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala. She is currently working under Cancer research program, RGCB, Kerala. Her research interest is in the area of Cancer biology and treatment.

S. Sreeja, is currently working as ScientistF at Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala. She completed her master’s (M.Sc) at Kerala university followed by PhD (biotechnology) from the same university. Her main research focus is to understand the role of estrogen and progesterone receptor interactions with specific agonist and antagonist. She is also working with phytoestrogens having SERM with endogenous SERM27 HC using in vivo and in vitro models. Her work related to pomegranate fruits draws attraction. Her work area of research is anti cancer drugs mechanism study.

S. R. Timane, completed his M. Pharm in Pharmacology specialization at Department of Pharmacology, PSG College of Pharmacy, Coimbatore, Tamil Nadu. He is currently working as Scientific Sales Executive, SANOFI, India. His area of research interest is Cancer biology, drug design and therapy.

M. Ram Pravin Kumar, completed his M. Pharm in Pharmacology specialization at Department of Pharmacology in PSG College of Pharmacy, Coimbatore, Tamil Nadu. He is currently working as Lecturer in Department of Pharmacology, PSG College of Pharmacy. His area of research interest is drug discovery and development and understanding the pathways related pathology of degenerative conditions.

S. Kabilan, is working as Professor of Chemistry in the Department of Chemistry Annamalai University Chidambaram. He is holding PhD degree in Organic chemistry. He is one of the pioneers in the field of organic chemical synthesis and got good reputation in his field of science. For Past 30 his research works involves synthesis of biologically active Organic compounds and reaction dynamics. Currently he is working on designing of active molecules using Schrodinger software, followed by synthesizing these active molecules for biological activity evaluation. He completed projects CSIR-2,DBT, DBT(NEC), ICMR and UGC. Recent Publications of his group display the expertise in synthetic organic chemistry and medicinal chemistry as well. Total research publication is 102.

M. Ramanathan, is working as a Principal/ Professor of Pharmacology and his field of specialization is Pharmacology. Recently he was awarded with DSc. Currently he is having three ongoing research projects from DST and DBT the total cost is Rs 133 lakhs and completed three projects with worth of 75 lakhs. He is guiding 6 PhD students. Total research paper published 53 in last five years Research paper published total 104 with H-index 28. His area of research interest is drug design and development of new chemical molecules for prostate cancer and understanding its mechanism of action. The pathways studied include AR, ERα and β, COX, GSK3β, TLR4. He also works in herbal preparation targeting these proteins. He is also evaluating the role of various inflammatory mediators and their pathways in neuroinflammation using neuronal cell culture and experimentally induced stroke model.

Additional information

Funding

This work is supported by the Department of Science and Technology SERB, Government of India (File No. SR/SO/HS/0135/2012).