Abstract
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) E2 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 PGE2 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-N6-(1-iminoethyl) lysine hydrochloride] and nonselective NOS inhibitor (Nω-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.
Footnotes
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This work was supported by the Life Science Research Board, Defense Research and Development Organization, Government of India [Grant LSRB/109/ID/2006] and Department of Science and Technology, Government of India [Grant SR/SO/HS-39/2005].
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doi:10.1124/jpet.108.145334.
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ABBREVIATIONS: PG, prostaglandin; COX, cyclooxygenase; HST-1, hydroxstilbene-1; BSA, bovine serum albumin; l-NIL, l-N6-(1-iminoethyl) lysine hydrochloride; l-NAME, Nω-nitro-l-arginine methyl ester; eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; PCR, polymerase chain reaction; DMSO, dimethyl sulfoxide; DS, damage score; MPO, myeloperoxidase; Ct, threshold cycle; vWF, von Willebrand factor; LVT, low-valent titanium; NOS, nitric oxide synthase.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received August 29, 2008.
- Accepted December 8, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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