title: The natural flavonoid apigenin sensitizes human CD44+prostate cancer stem cells to cisplatin therapy.
abstract: Prostate cancer (PCa) is the second most common type of cancer and the fifth leading cause of cancer-related death among men. Development of chemoresistance, tumor relapse and metastasis remain major barriers to effective treatment and all been identified to be associated with cancer stem cells (CSCs). Natural flavonoids such as apigenin have been shown to have the ability to improve the therapeutic efficacy of common chemotherapy agents through CSCs sensitization. Thus, the aim of this study was to evaluate the combination of apigenin with cisplatin on CD44+PCa stem cell growth and migration. Platinum-based anti-neoplastic drugs have been used to treat a number of malignancies including PCa. However, acquired resistance and side effects unfortunately have limited cisplatin's use. A CD44+subpopulation was isolated from human androgen-independent PC3 PCa cells by using human CD44-PE antibody. IC50values were determined by MTT test. RT-qPCR, Western blot analyses and image-based cytometer were used to investigate apoptosis, cell cycle and their underlying molecular mechanisms. Cell migration was evaluated by wound healing test. The combination of the IC50doses of apigenin (15μM) and cisplatin (7.5μM) for 48h significantly enhanced cisplatin's cytotoxic and apoptotic effects through downregulation of Bcl-2, sharpin and survivin; and upregulation of caspase-8, Apaf-1 and p53 mRNA expression. The combined therapy suppressed the phosphorylation of p-PI3K and p-Akt, inhibited the protein expression of NF-κB, and downregulated the cell cycle by upregulating p21, as well as cyclin dependent kinases CDK-2, -4, and -6. Apigenin significantly increased the inhibitory effects of cisplatin on cell migration via downregulation of Snail expression. In conclusion, our study showed the possible therapeutic approach of using apigenin to potentially increase the effects of cisplatin by targeting CSCs subset in prostate cancer.
authors.affiliation: Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Turkey. Electronic address: suaterdogan@trakya.edu.tr.
authors.forename: Suat
authors.initials: S
authors.lastname: Erdogan
authors.affiliation: Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Turkey. Electronic address: kader_turkekul@hotmail.com.
authors.forename: Kader
authors.initials: K
authors.lastname: Turkekul
authors.affiliation: Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Turkey. Electronic address: rizaserttas@trakya.edu.tr.
authors.forename: Rıza
authors.initials: R
authors.lastname: Serttas
authors.affiliation: Department of Food Processing, Vocational Collage of Arda, Aysekadin Campus, Trakya University, Balkan Campus, Edirne, Turkey. Electronic address: zeyneperdogan@trakya.edu.tr.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Erdogan
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D047310:Apigenin / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use*; D006801:Humans; D018960:Hyaluronan Receptors / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D009363:Neoplasm Proteins; D047310:Apigenin; D002945:Cisplatin
keywords: Apigenin; CD44(+); Cisplatin; Prostate cancer; Stem cells