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Combination of 2-methoxyestradiol (2-ME2) and eugenol for apoptosis induction synergistically in androgen independent prostate cancer cells |
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| Authors: | Rita Ghosh Manonmani Ganapathy William L. Alworth Daniel C. Chan Addanki P. Kumar |
| Affiliation: | 1. Department of Urology, School of Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, United States;2. Department of Chemistry, Tulane University, New Orleans, United States;3. Department of Medical Oncology, University of Colorado Health Science Center, Denver, CO, United States;1. Department of Traditional Chinese Medicine, Children''s Hospital of Fudan University, Shanghai 201102, China;2. Department of Nephrology, Children''s Hospital of Fudan University, Shanghai 201102, China;3. Pediatric Institute, Children''s Hospital of Fudan University, Shanghai 201102, China;4. Department of Pathology, Shanghai medical college of Fudan University, Shanghai 200032, China;1. Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi, India;2. Cancer Pharmacology Division, Indian Institute of Integrative Medicine, CSIR, Jammu 180001, India;3. Instrumentation Division, Indian Institute of Integrative Medicine, CSIR, Jammu 180001, India;4. Microbial Biotechnology Division, Indian Institute of Integrative Medicine, CSIR, Jammu 180001, India;5. PK-PD-Toxicology Division, Indian Institute of Integrative Medicine, CSIR, Jammu 180001, India;6. Genetic Resources & Agrotech Division, Indian Institute of Integrative Medicine, CSIR, Jammu 180001, India;1. Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi, India;2. Department of Radiation Oncology, Maulana Azad Medical College, New Delhi, India;3. Department of Medical Oncology, All India Institute of Medical Sciences (AIIMS), New Delhi, India;4. Department of Biosciences, Jamia Millia Islamia, New Delhi, India |
| Abstract: | Lack of effective treatment options for the management of hormone refractory prostate cancer (PCA) reinforce the great need to develop novel compounds that act singly or in combination. 2-Methoxyestradiol (2-ME2) is an endogenous estrogenic metabolite that has been reported to work as an antiproliferative agent in various tumor models including prostate. Recently conducted clinical trial in hormone refractory prostate cancer (HRPC) patients concluded that 2-ME2 was safe and well tolerated. However this study identified bioavailability of 2-ME2 as a limiting factor. Here we report the ability of a combination of 2-ME2 and eugenol (4-allyl-2-methoxyphenol) as an approach for enhancing anticancerous activities in prostate cancer cells. Combining 2-ME2 with eugenol (i) inhibited growth of prostate cancer cells and induced apoptosis at lower concentrations than either single agent alone; (ii) analysis of the data using combination index (CI) showed CI values of 0.4 indicating strong synergistic interaction; (iii) increased population of cells G2/M phase by 4.5-fold (p = 0.01); (iv) significantly reduced expression of antiapoptotic protein Bcl-2 and enhanced expression of proapoptotic protein Bax. Combination induced apoptosis was not affected in PC-3 cells that over-express or lack Bcl-2 but was associated with loss of mitochondrial membrane potential. Since 2-ME2 was well tolerated in phase II trail in patients with HRPC; and eugenol is consumed by humans in the form of spices, the combination of 2-ME2 with eugenol may offer a new clinically relevant treatment regimen. Combining these agents may allow ameliorating any adverse effects of either 2-ME2 or eugenol alone by reducing their individual concentrations should these two agents be developed for human use. |
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