Androstane derivatives induce apoptotic death in MDA-MB-231 breast cancer cells.
Biological investigation was conducted to study in vitro antiproliferative and pro-apoptotic potential of selected 17α-picolyl and 17(E)-picolinylidene androstane derivatives. The antiproliferative impact was examined on six human tumor cell lines, including two types of breast (MCF-7 and MDA-MB-231), prostate (PC3), cervical (HeLa), colon (HT 29) and lung cancer (A549), as well as one normal fetal lung fibroblasts cell line (MRC-5). All derivatives selectively decreased proliferation of estrogen receptor negative MDA-MB-231 breast cancer cells after 48 h and 72 h treatment and compounds showed time-dependent activity. We used this cell line to investigate cell cycle modulation and apoptotic cell death induction by flow cytometry, expression of apoptotic proteins by Western blot and apoptotic morphology by visual observation. Tested androstane derivatives affected the cell cycle distribution and induced apoptosis and necrosis. Compounds had different and specific mode of action, depending on derivative type and exposure time. Some compounds induced significant apoptosis measured by Annexin V test compared to reference compound formestane. Higher expression of pro-apoptotic BAX, downregulation of anti-apoptotic Bcl-2 and cleavage of PARP protein were confirmed in almost all treated samples, but the lack of caspase-3 activation suggested the induction of apoptosis in caspase-independent manner. More cells with apoptotic morphology were observed in samples after prolonged treatment. Structure-activity relationship analysis was performed to find correlations between the structure variations of investigated derivatives and observed biological effects. Results of this study showed that some of the investigated androstane derivatives have good biomedical potential and could be candidates for anticancer drug development.
Oncology Institute of Vojvodina, Put Doktora Goldmana 4, 21204 Sremska Kamenica, Serbia. Electronic address: jakimov.dimitar@onk.ns.ac.rs.
Dimitar S
DS
Jakimov
Oncology Institute of Vojvodina, Put Doktora Goldmana 4, 21204 Sremska Kamenica, Serbia.
Vesna V
VV
Kojić
Oncology Institute of Vojvodina, Put Doktora Goldmana 4, 21204 Sremska Kamenica, Serbia.
Lidija D
LD
Aleksić
Oncology Institute of Vojvodina, Put Doktora Goldmana 4, 21204 Sremska Kamenica, Serbia.
Gordana M
GM
Bogdanović
Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
Jovana J
JJ
Ajduković
Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
Evgenija A
EA
Djurendić
Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
Katarina M
KM
Penov Gaši
Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
Marija N
MN
Sakač
Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
Suzana S
SS
Jovanović-Šanta
D000731:Androstanes / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000731:Androstanes; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; C033936:androstane
17(E)-Picolinylidene androstane derivatives; 17α-Picolyl androstane derivatives; Antiproliferative effect; Apoptosis induction; Breast cancer cell lines