In vitro and in vivo studies on stilbene analogs as potential treatment agents for colon cancer.
Based on the potential of resveratrol as a colon cancer chemopreventive agent, a set of 26 stilbenes were synthesized and tested against the colon cancer cell lines HT-29 and Caco-2. (Z)-4-(3,5-Dimethoxystyryl)aniline (4), (Z)-methyl-4-(3,5-dimethoxystyryl)benzoate (6), and (Z)-1,3-dimethoxy-5-(4-methoxystyryl)benzene (10) showed strong inhibitory activity in vitro. In vivo studies using HT-29 xenografts in immunodeficient mice were conducted with 4, 6 and 10, together with their corresponding trans isomers (3, 5, and 9, respectively), at the dose of 10 mg/kg body weight. Tumor volume was significantly lowered in 3-, 4-, and 9-treated groups. The cis- and trans-amino analogs (4 and 3, respectively) had similar effect on tumor growth, a 40% decrease compared to the control. Analysis of the serum revealed that 4 isomerized to 3, which may explain their similar effects in SCID mice. Stilbenes 5, 6, 9, and 10 retained their configurations in the serum. Stilbenes 6 and 10 lacked tumor-suppressive effect in SCID mice; the serum levels of these analogs were low (18.8 and 15.5 ng/mL, respectively). Stilbene 9, while weakly active in vitro demonstrated good activity in vivo, was found at higher levels in the serum (69.9 ng/mL) compared to 10. The anti-tumorigenic activity of these stilbene analogs may be partly linked to their effects on proteins involved in cell proliferation, as observed by lowered expression of proliferating cell nuclear antigen and upregulation of the cyclin-dependent kinase inhibitor, p27, in the tumor tissues. Overall, identification of the anti-tumorigenic potential of these compounds provides opportunities for their use against colorectal cancer.
Paul
Shiby
S
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Mizuno
Cassia S
CS
Lee
Hong Jin
HJ
Zheng
Xi
X
Chajkowisk
Sarah
S
Rimoldi
John M
JM
Conney
Allan
A
Suh
Nanjoo
N
Rimando
Agnes M
AM
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D013267:Stilbenes / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018809:Proliferating Cell Nuclear Antigen; D013267:Stilbenes