title: Caffeic acid phenethyl ester synergistically enhances docetaxel and paclitaxel cytotoxicity in prostate cancer cells.
abstract: Evidence is growing for the beneficial role of selective estrogen receptor modulators (SERM) in prostate diseases. Caffeic acid phenethyl ester (CAPE) is a promising component of propolis that possesses SERM activity. This study aimed at investigating the modulatory impact of CAPE on docetaxel (DOC) and paclitaxel (PTX) cytotoxicity in prostate cancer cells and exploring the possible underlying mechanisms for this chemomodulation. CAPE significantly increased DOC and PTX potency in PC-3, DU-145 and LNCaP prostate cancer cells. Combination index calculations showed synergistic interaction of CAPE/DOC and CAPE/PTX cotreatments in all the tested cell lines. Subsequent mechanistic studies in PC-3 cells indicated that cyclin D1 and c-myc were significantly reduced in the combined treatment groups with concurrent increase in p27kip. DNA-ploidy analysis indicated a significant increase in the percentage of cells in pre-G1 in CAPE/DOC and CAPE/PTX cotreatments. Decreased Bcl-2/Bax ratio together with increased caspase-3 activity and protein abundance were observed in the same groups. Estrogen receptor-β (ER-β) and its downstream tumor suppressor forkhead box O1 levels were significantly elevated in CAPE and combination groups compared to DOC or PTX-alone. ER-α and insulin-like growth factor-1 receptor protein abundance were reduced in the same groups. CAPE significantly reduced AKT, ERK and ER-α (Ser-167) phosphorylation in PC-3 cells. CAPE-induced inhibition of AKT phosphorylation was more prominent (1.7-folds higher) in cells expressing ER-α such as PC-3 compared to LNCaP. In conclusion, CAPE enhances the antiproliferative and cytotoxic effects of DOC and PTX in prostate cancer cells. This can be, at least partly, attributed to CAPE augmentation of DOC and PTX proapoptotic effects in addition to CAPE-induced alterations in ER-α and ER-β abundance.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Mai F
authors.initials: MF
authors.lastname: Tolba
authors.forename: Ahmed
authors.initials: A
authors.lastname: Esmat
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Al-Abd
authors.forename: Samar S
authors.initials: SS
authors.lastname: Azab
authors.forename: Amani E
authors.initials: AE
authors.lastname: Khalifa
authors.forename: Hisham A
authors.initials: HA
authors.lastname: Mosli
authors.forename: Sherif Z
authors.initials: SZ
authors.lastname: Abdel-Rahman
authors.forename: Ashraf B
authors.initials: AB
authors.lastname: Abdel-Naim
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002109:Caffeic Acids / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D004357:Drug Synergism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D017239:Paclitaxel / Q000627:therapeutic use*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D043823:Taxoids / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D002109:Caffeic Acids; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D043823:Taxoids; D000077143:Docetaxel; D053148:Caspase 3; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol; D017239:Paclitaxel
keywords: caffeic acid phenethyl ester; estrogen receptors; prostate cancer; taxanes