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Growth inhibitory effects of diallyl disulfide on human breast cancer cell lines
H Nakagawa1, K Tsuta, K Kiuchi
1Department of Pathology II and Department of Surgery II, Kansai Medical University, Moriguchi, Osaka 570-8506, Japan.
Abstract:
Diallyl disulfide (DADS) is an oil-soluble organosulfur compound found in garlic. The effect of synthetic DADS on the growth of estrogen receptor (ER)-positive (KPL-1 and MCF-7) and -negative (MDA-MB-231 and MKL-F) human breast cancer cell lines was examined. In an in vitro MTT assay, regardless of ER status, DADS at an IC(50) of 1.8-18.1 microM after 72 h incubation caused inhibition of growth in all four cell lines examined. Growth inhibition was due to apoptosis as seen by the appearance of a sub G1 fraction. In MDA-MB-231 cells, the apoptosis cascade comprised up-regulation of Bax protein (142%), down-regulation of Bcl-X(L) protein (38%) and activation of caspase-3 (438%) compared with controls. In an in vivo assay by orthotopic (right thoracic mammary fat pad) transplantation of KPL-1 cells in female nude mice, intraperitoneal injection of 1 or 2 mg DADS three times a week from the day of tumor cell inoculation until the end of the experiment (after 35 days) caused growth retardation and 43% reductions in primary tumor weight, respectively, compared with DADS-untreated mice without apparent side effects. Cell proliferation as evaluated by proliferating cell nuclear antigen (PCNA)-labeling in transplanted tumor of DADS-untreated mice was 59.6%, and 1 and 2 mg DADS-treated mice was 44.6 and 44.5%, respectively. In MDA-MB-231 cells, DADS antagonized the effect of linoleic acid (LA), a potent breast cancer cell stimulator (at DADS = 1.8 microM and LA > or = 6.5x10(2) microM concentration), and synergized the effect of eicosapentaenoic acid (EPA), a potent breast cancer cell suppressor (at DADS >3 x 10(-3) microM and EPA > 6.3 x 10(-1) microM concentration). Thus, DADS could be a promising anticancer agent for both hormone-dependent and -independent breast cancers, and may harmonize with polyunsaturated fatty acids known as modulators of breast cancer cell growth.
Insights
Diallyl disulfide (DADS), a compound found in garlic, effectively inhibits human breast cancer cell growth, both estrogen receptor-positive and -negative, by inducing apoptosis. DADS shows promise as an anticancer agent, demonstrating efficacy in both in vitro and in vivo models.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Diallyl disulfide (DADS) is an organosulfur compound present in garlic with potential therapeutic properties.
- Breast cancer encompasses diverse subtypes, including estrogen receptor (ER)-positive and -negative, necessitating varied treatment strategies.
- Understanding the mechanisms of novel compounds like DADS in modulating cancer cell proliferation is crucial for developing new therapies.
Purpose of the Study:
- To investigate the anti-cancer effects of synthetic DADS on various human breast cancer cell lines.
- To determine the impact of DADS on cell growth, apoptosis, and proliferation in both in vitro and in vivo settings.
- To explore the interaction of DADS with specific fatty acids in modulating breast cancer cell behavior.
Main Methods:
- In vitro MTT assays were conducted on ER-positive (KPL-1, MCF-7) and ER-negative (MDA-MB-231, MKL-F) human breast cancer cell lines to assess DADS's cytotoxic effects.
- Apoptosis was analyzed by flow cytometry (sub G1 fraction) and Western blotting for key proteins (Bax, Bcl-X(L), caspase-3) in MDA-MB-231 cells.
- In vivo efficacy was evaluated using orthotopic transplantation of KPL-1 cells in nude mice, with DADS administered intraperitoneally, and tumor growth/proliferation (PCNA-labeling) assessed.
Main Results:
- DADS demonstrated significant growth inhibition across all tested cell lines, irrespective of ER status, with IC(50) values ranging from 1.8-18.1 microM after 72 hours.
- Growth inhibition was attributed to apoptosis induction, evidenced by sub G1 fraction increase and modulation of apoptosis-related proteins (Bax, Bcl-X(L), caspase-3).
- In vivo studies showed DADS significantly reduced primary tumor weight and cell proliferation (PCNA-labeling) in mice without apparent side effects. DADS also modulated the effects of linoleic acid and eicosapentaenoic acid on cancer cells.
Conclusions:
- Diallyl disulfide exhibits potent anticancer activity against both hormone-dependent and -independent human breast cancer cells.
- DADS induces apoptosis and reduces tumor growth and proliferation, suggesting its potential as a therapeutic agent.
- DADS may synergize with certain polyunsaturated fatty acids, offering a potential complementary therapeutic strategy for breast cancer management.