A novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits colon tumor cell growth and induces apoptosis with antitumor activity.
Nonsteroidal anti-inflammatory drugs such as sulindac have shown promising antineoplastic activity, although toxicity from cyclooxygenase (COX) inhibition and the suppression of prostaglandin synthesis limits their use for chemoprevention. Previous studies have concluded that the mechanism responsible for their antineoplastic activity may be COX independent. To selectively design out the COX inhibitory activity of sulindac sulfide (SS), in silico modeling studies were done that revealed the crucial role of the carboxylate moiety for COX-1 and COX-2 binding. These studies prompted the synthesis of a series of SS derivatives with carboxylate modifications that were screened for tumor cell growth and COX inhibitory activity. A SS amide (SSA) with a N,N-dimethylethyl amine substitution was found to lack COX-1 and COX-2 inhibitory activity, yet potently inhibit the growth of human colon tumor cell lines, HT-29, SW480, and HCT116 with IC(50) values of 2 to 5 micromol/L compared with 73 to 85 micromol/L for SS. The mechanism of growth inhibition involved the suppression of DNA synthesis and apoptosis induction. Oral administration of SSA was well-tolerated in mice and generated plasma levels that exceeded its in vitro IC(50) for tumor growth inhibition. In the human HT-29 colon tumor xenograft mouse model, SSA significantly inhibited tumor growth at a dosage of 250 mg/kg. Combined treatment of SSA with the chemotherapeutic drug, Camptosar, caused a more sustained suppression of tumor growth compared with Camptosar treatment alone. These results indicate that SSA has potential safety and efficacy advantages for colon cancer chemoprevention as well as utility for treating malignant disease if combined with chemotherapy.
Piazza
Gary A
GA
Drug Discovery and Development Divisions, Southern Research Institute, Birmingham, Alabama 35205, USA. piazza@sri.org
Keeton
Adam B
AB
Tinsley
Heather N
HN
Gary
Bernard D
BD
Whitt
Jason D
JD
Mathew
Bini
B
Thaiparambil
Jose
J
Coward
Lori
L
Gorman
Gregory
G
Li
Yonghe
Y
Sani
Brahma
B
Hobrath
Judith V
JV
Maxuitenko
Yulia Y
YY
Reynolds
Robert C
RC
D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology / Q000637:transplantation; D003110:Colonic Neoplasms / Q000473:pathology*; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000032:analysis; D011487:Protein Conformation; D013467:Sulindac / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D009363:Neoplasm Proteins; C543001:sulindac sulfide amide; D013467:Sulindac; D000077146:Irinotecan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D002166:Camptothecin