Improved antiulcer and anticancer properties of a trans-resveratrol analog in mice.
Despite its potential, use of trans-resveratrol as an anticancer drug is severely constrained because of its tendency to prolong gastric ulceration. We found that in addition to delaying ulcer healing, trans-resveratrol also aggravated acute gastric ulceration induced by the nonsteroidal anti-inflammatory drugs by reducing the synthesis of prostaglandin (PG) E(2) via a specific inhibition of cyclooxygenase (COX)-1 that also hampered angiogenesis. However, for the first time, we showed that the 3'-5'-hydroxylated congener [(E)-HST-1] of trans-resveratrol, synthesized in multigram scale, exerted potential chemotherapeutic property but was nonulcerogenic in nature, rather moderately accelerated healing of indomethacin-induced gastric ulceration. HST-1 did not suppress COX-1, COX-2 expression, and PGE(2) synthesis but reduced the level of inflammatory myeloperoxidase (MPO) activity. The healing was augmented primarily through the nitric oxide synthase (NOS)-dependent pathway. HST-1 treatment induced endothelial NOS (eNOS) expression and reduced inducible NOS (iNOS), resulting in increased eNOS/iNOS ratio. The selective iNOS inhibitor [L-N(6)-(1-iminoethyl) lysine hydrochloride] and nonselective NOS inhibitor (N(omega)-nitro-L-arginine methyl ester) treatment revealed that eNOS could be the probable molecular switch to accelerate the indomethacin-induced ulcer healing in HST-1-treated mice. Furthermore, the anticancer effect of HST-1 on U937 and K562 leukemia cell lines was found to be significantly better than that of trans-resveratrol. Overall, these established HST-1 as a potentially better anticancer compound than trans-resveratrol, considering it is devoid of any ulcerogenic side effects. In conclusion, for the first time, we showed that a novel analog of trans-resveratrol, HST-1, was devoid of ulcerogenic adversative effects of trans-resveratrol but retained potentially better anticancer property.
Guha
Prasun
P
Department of Biochemistry, Dr. B.C. Roy Postgraduate Institute of Basic Medical Sciences and Institute of Post Graduate Medical Education & Research (I.P.G.M.&R.), Kolkata, India.
Dey
Anindya
A
Sarkar
Biswanath
B
Dhyani
Manish V
MV
Chattopadhyay
Subrata
S
Bandyopadhyay
Sandip K
SK
D000818:Animals; D000897:Anti-Ulcer Agents / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D051545:Cyclooxygenase 1 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D016595:Misoprostol / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D000077185:Resveratrol; D013267:Stilbenes / Q000627:therapeutic use*; D013270:Stomach / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D014945:Wound Healing / Q000187:drug effects
D000897:Anti-Ulcer Agents; D000970:Antineoplastic Agents; D013267:Stilbenes; D016595:Misoprostol; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000077185:Resveratrol; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin