Growth inhibitory effects of diallyl disulfide on human breast cancer cell lines.
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.
Nakagawa
H
H
Department of Pathology II and Department of Surgery II, Kansai Medical University, Moriguchi, Osaka 570-8506, Japan.
Tsuta
K
K
Kiuchi
K
K
Senzaki
H
H
Tanaka
K
K
Hioki
K
K
Tsubura
A
A
D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001095:Arachidonic Acids / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004032:Diet; D004220:Disulfides / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D019787:Linoleic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008207:Lymphatic Metastasis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011960:Receptors, Estrogen / Q000502:physiology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000498:Allyl Compounds; D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D004220:Disulfides; D006131:Growth Inhibitors; D011960:Receptors, Estrogen; C028009:diallyl disulfide; D019787:Linoleic Acid