Androstane derivatives induce apoptotic death in MDA-MB-231 breast cancer cells
Dimitar S Jakimov1, Vesna V Kojić1, Lidija D Aleksić1
1Oncology Institute of Vojvodina, Put Doktora Goldmana 4, 21204 Sremska Kamenica, Serbia.
Abstract:
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.
Insights
New androstane derivatives show promise as anticancer drugs by selectively inhibiting cancer cell proliferation and inducing apoptosis. These compounds demonstrate time-dependent activity and a caspase-independent mechanism, highlighting their potential for future drug development.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Pharmacology
Background:
- Androstane derivatives are being explored for their therapeutic potential.
- Understanding their antiproliferative and pro-apoptotic effects is crucial for drug development.
Purpose of the Study:
- To investigate the in vitro antiproliferative and pro-apoptotic effects of novel 17α-picolyl and 17(E)-picolinylidene androstane derivatives.
- To evaluate the efficacy of these derivatives against various human tumor cell lines, including breast, prostate, cervical, colon, and lung cancer.
- To elucidate the mechanism of action, including cell cycle modulation, apoptosis induction, and protein expression changes.
Main Methods:
- In vitro antiproliferative assays on six human tumor cell lines and one normal cell line.
- Flow cytometry for cell cycle analysis and apoptosis detection (Annexin V assay).
- Western blot analysis for apoptotic protein expression (BAX, Bcl-2, PARP) and morphological assessment.
Main Results:
- Selected androstane derivatives selectively reduced proliferation in estrogen receptor-negative MDA-MB-231 breast cancer cells in a time-dependent manner.
- Derivatives induced apoptosis and necrosis, affecting cell cycle distribution.
- Increased BAX and cleaved PARP, with decreased Bcl-2 expression, indicating apoptosis.
- Apoptosis occurred via a caspase-independent pathway, with increased apoptotic morphology upon prolonged treatment.
Conclusions:
- The investigated androstane derivatives exhibit significant antiproliferative and pro-apoptotic activities against cancer cells.
- These compounds demonstrate potential as candidates for anticancer drug development due to their selective action and novel mechanism.
- Structure-activity relationship analysis provides insights for optimizing future derivative design.
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