Inhibition of Ribonucleotide Reductase Induces Endoplasmic Reticulum Stress and Apoptosis, Leading to the Death of Docetaxel-resistant Prostate Cancer Cells
Küçük Resim Yok
Tarih
2023
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Bentham Science Publ Ltd
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
Background The development of chemotherapy resistance in prostate cancer (PCa) patients poses a significant obstacle to disease progression. Ribonucleotide reductase is a crucial enzyme for cell division and tumor growth. Triapine, an inhibitor of ribonucleotide reductase, has shown strong anti-tumor activity in various types of cancers. However, the effect of triapine on docetaxel-resistant (DR) human PCa cells has not been explored previously.Aim This study aimed to examine the potential anti-proliferative effects of triapine in PC3-DR (docetaxel-resistant) cells.Methods Cell viability was determined by the MTT test, and apoptosis and cell cycle progression were analyzed by image-based cytometer. mRNA and protein expression were assessed by RT-qPCR and western blot, respectively.Results Triapine administration significantly reduced PC3 and PC3-DR cells' survival, while the cytotoxic effect was higher in PC3-DR cells. Cell death resulting from inhibition of ribonucleotide reductase was mediated by endoplasmic reticulum stress, induction of apoptosis, and cell cycle arrest. The findings were supported by the upregulation of caspases, Bax, Bak, P21, P27, P53, TNF-alpha, FAS, and FASL, and downregulation of Bcl2, Bcl-XL, cyclin-dependent kinase 2 (CDK2), CDK4, cyclins, and heat shock proteins expression. According to the data, the reduction of ABC transporter proteins and NF-kappa B expression may play a role in triapine-mediated cytotoxicity in docetaxel-resistant cells.Conclusion Based on our findings, triapine emerges as a promising chemotherapeutic approach for combating docetaxel-resistant prostate cancer.
Açıklama
Anahtar Kelimeler
Apoptosis, Docetaxel, Endoplasmic Reticulum, Prostate Cancer, PC3, Triapine, Drug-Resistance, In-Vitro, Phase-I, Triapine, Combination, Chemotherapy, Mechanisms
Kaynak
Anti-Cancer Agents In Medicinal Chemistry
WoS Q Değeri
N/A
Scopus Q Değeri
Q3
Cilt
23
Sayı
17
