title: Acetazolamide triggers death inducing autophagy in T-47D breast cancer cells.
abstract: The inhibitory effects of acetazolamide on the growth and proliferation of epithelial breast cancer cells (T-47D) were investigated. Analysis of morphological changes indicated little apoptosis in T-47D cells incubated with acetazolamide, according to data from flow cytometry, DNA laddering, and expression of AIF. However, an increase in caspase-3 activity was detected in cells. This was concomitant with an increase in DFF45/DFF40 ratio leading to inhibition of caspase-3 activity, DNA fragmentation and progression of apoptosis. Flow cytometry also confirmed that acetazolamide had no significant effect on cell cycle progression. These results are consistent with lack of change in the expression of cell cycle regulatory proteins p21, p27, cdc2 and cyclinD1. Increased expression of ATG5, p53 and DRAM, along with an increase in BCLN1/Bcl-2 ratio, indicated that acetazolamide inhibited the proliferation of T-47D cells by inducing autophagy. Increased expression of PTEN, along with decreased expression of Akt1, also showed that acetazolamide treatment resulted in death inducing autophagy. Collectively the results indicate that autophagy is an adequate mechanism mediating the anti-cancer effects of acetazolamide in T-47D cells through engagement of p53/DRAM pathway and attenuation of Akt survival signalling.
authors.affiliation: Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
authors.forename: Raziye
authors.initials: R
authors.lastname: Mohammadpour
authors.forename: Shahrokh
authors.initials: S
authors.lastname: Safarian
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Ejeian
authors.forename: Zahra
authors.initials: Z
authors.lastname: Sheikholya-Lavasani
authors.forename: Mohammad Hossein
authors.initials: MH
authors.lastname: Abdolmohammadi
authors.forename: Nader
authors.initials: N
authors.lastname: Sheinabi
mesh_terms: D000086:Acetazolamide / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D000086:Acetazolamide
keywords: acetazolamide; apoptosis; autophagy; breast cancer