Diallyl disulfide causes caspase-dependent apoptosis in human cancer cells through a Bax-triggered mitochondrial pathway.
Diallyl disulfide (DADS), an important component of garlic (Allium sativum) derivative, has been demonstrated to exert a potential molecular target against human cancers. We investigated DADS-induced expressions of Apaf1, cystatin B, caspase-3 and FADD (fas-associated protein with death domain) in breast, prostate and lung cancer cells. These showed coincident data when further examined by quantitative reverse transcription-polymerase chain reaction and Western blot analysis. Furthermore, DADS induced a marked amount of Bax translocation, cytochrome c release and activation of caspase-3 and caspase-9. DADS-treated tumor cells triggered mitochondria-mediated signaling pathways that led to a significant increase in apoptosis induction. Further studies with caspase-3 and caspase-9 inhibitors (zDEVD-fmk and zLEHD-fmk, respectively) proved that DADS induces apoptosis through a caspase-3-dependent pathway. DADS is only an agent used in the study. The molecular mechanism presented therefore provides strong additional support to the hypothesis that DADS is a strong inducer of apoptosis through a Bax-triggered mitochondria-mediated and caspase-3-dependent pathway. This study shows clearly that DADS causes caspase-dependent apoptosis in human cancer cells through a Bax-triggered mitochondrial pathway. Therefore, the mitochondrial pathway might be the target for cancer chemoprevention and/or chemotherapy by DADS.
Nagaraj
Nagathihalli S
NS
Division of Surgical Oncology, Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. nagaraj.nagathihalli@vanderbilt.edu
Anilakumar
Kandangath R
KR
Singh
Om V
OV
D000498:Allyl Compounds / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D018890:Chemoprevention; D055313:Cystatin B / Q000235:genetics / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004220:Disulfides / Q000494:pharmacology*; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D005737:Garlic / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D018517:Plant Roots / Q000737:chemistry; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
C506592:APAF1 protein, human; D000498:Allyl Compounds; D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; D053477:Apoptotic Protease-Activating Factor 1; C494826:BAX protein, human; C524994:CSTB protein, human; D061945:Caspase Inhibitors; D004220:Disulfides; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D051028:bcl-2-Associated X Protein; C028009:diallyl disulfide; D055313:Cystatin B; D045304:Cytochromes c; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9