Antiproliferative effect of natural tetrasulfides in human breast cancer cells is mediated through the inhibition of the cell division cycle 25 phosphatases.
For many years, in vitro and in vivo studies have reported that organosulfur compounds (OSCs), naturally found in Allium vegetables, are able to suppress the proliferation of various tumor cells. In spite of recent advances, the specific molecular mechanisms involved in OSC activity are still unclear. Considering the antiproliferative effects observed in cancer cells, we postulated that OSCs might target the cell division cycle (Cdc) 25 phosphatases which are crucial enzymes of the cell cycle. Our findings suggest phosphatases Cdc25 as possible targets of naturally occuring polysulfides contributing to their anticancer properties. We report on the inhibitory activity of tetrasulfides occurring naturally in garlic and onion towards the human Cdc25 phosphatases. Diallyl- and dipropyltetrasulfides have emerged as interesting irreversible inhibitors of the Cdc25 isoforms A and C in vitro. Furthermore, growth of both sensitive (MCF-7) and resistant (Vcr-R) human breast carcinoma cells was significantly decreased by these tetrasulfides. The observed antiproliferative effect appeared to be associated with a G2-M cell cycle arrest.
Laboratoire d'Ingénierie Moléculaire et Biochimie Pharmacologique, EA 3940, FR CNRS 2843, UFR SciFA, Rue du Général Delestraint, 57070 Metz, France.
Elodie
E
Viry
Awais
A
Anwar
Gilbert
G
Kirsch
Claus
C
Jacob
Marc
M
Diederich
Denyse
D
Bagrel
D000498:Allyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D057075:Enzyme Assays; D005260:Female; D005737:Garlic; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000302:isolation & purification; D019697:Onions; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification; D013440:Sulfides / Q000138:chemical synthesis / Q000494:pharmacology*; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification
D000498:Allyl Compounds; D000970:Antineoplastic Agents; D007527:Isoenzymes; D011994:Recombinant Proteins; D013440:Sulfides; C560444:dipropyl tetrasulfide; D016203:CDC2 Protein Kinase; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D020687:cdc25 Phosphatases; C431585:diallyl tetrasulfide