Therapeutic potential of gossypol: An overview

Neghab, Hoda Keshmiri; Goliaei, Bahram

doi:10.3109/13880209.2013.832776

Cited by 107 publications

(69 citation statements)

References 48 publications

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“…In addition to its contraceptive property, gossypol is known to possess many other biological effects such as anti-HIV and anti-malarial properties (Polsky et al, 1989;Razakantoanina et al, 2000). In recent years, the anticancer properties of gossypol have been extensively studied (Keshmiri-Neghab & Goliaei, 2014;Soderquist et al, 2013;Zhang et al, 2010). The mechanisms of anticancer action include decrease of anti-apoptotic genes (e.g.…”

Section: Introductionmentioning

confidence: 99%

Identification of glucuronidation and biliary excretion as the main mechanisms for gossypol clearance:in vivoandin vitroevidence

Sun

et al. 2014

Xenobiotica

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1. The natural polyphenol gossypol possesses many therapeutic benefits. Here we aim to determine the elimination pathways of gossypol in vivo and in vitro. 2. Metabolite elucidation of gossypol was performed using UPLC-QTOF/MS coupled with Metabolynx analysis. Clearance of gossypol was evaluated in bile duct cannulated rats and in the single-pass perfused rat intestine model. In vitro glucuronidation of gossypol was characterized using liver and intestine microsomes as well as recombinant UDP-glucuronosyltransferase (UGT) enzymes. 3. Analysis of rat plasma, urine, and feces revealed glucuronidation as the only metabolic pathway for gossypol. In bile duct cannulated rats, considerable amounts of glucuronides (G1, G2 and G3; 58.8-83.2% of dose) and parent compound (5.0-20%) were excreted into bile after IV administration. In the perfused rat intestine model, gossypol was well absorbed with a [Formula: see text] (the dimensionless effective permeability) value of 4.4. Significant amounts of glucuronides (G1, G2 and G3) were excreted into the gut lumen (2.5%) and into the bile (4.8%). Biliary excretion of unchanged gossypol (6.0%) was comparable to that of glucuronides. Further, gossypol was subjected to rapid glucuronidation by liver and intestine microsomes. Reaction phenotyping showed that multiple UGT1A enzymes (including UGT1A1, 1A3, 1A7 and 1A8) are mainly responsible for gossypol metabolism. 4. In conclusion, glucuronidation was the only metabolic pathway for gossypol in rats. Excretion of unchanged gossypol into bile was also an important clearance mechanism.

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Section: Introductionmentioning

confidence: 99%

Identification of glucuronidation and biliary excretion as the main mechanisms for gossypol clearance:in vivoandin vitroevidence

Sun

et al. 2014

Xenobiotica

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“…Gossypol (Gos) is a promising anticancer agent presently under clinical trial (15). Gos is a natural polyphenol compound extracted from cottonseeds (16), which was initially investigated in China as a male contraceptive agent (17).…”

Section: Introductionmentioning

confidence: 99%

Gossypol induces apoptosis in multiple myeloma cells by inhibition of interleukin-6 signaling and Bcl-2/Mcl-1 pathway

Sadahira

Sagawa

Nakazato

et al. 2014

International Journal of Oncology

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Multiple myeloma (MM) is a clonal plasma cell disorder affecting the immune system with various systemic symptoms. MM remains incurable even with high dose chemotherapy using conventional drugs, thus necessitating development of novel therapeutic strategies. Gossypol (Gos) is a natural polyphenolic compound extracted from cotton plants, and has been shown to possess anti-neoplastic activity against various tumors. Recent studies have shown that Gos is an inhibitor for Bcl-2 or Bcl-XL acting as BH3 mimetics that interfere interaction between pro-apoptotic BH3-only proteins and Bcl-2/Bcl-XL. Since most of the patients with MM overexpress Bcl-2 protein, we considered Gos might be a promising therapeutic agent for MM. We herein show that Gos efficiently induced apoptosis and inhibited proliferation of the OPM2 MM cell line, in a dose- and time-dependent manner. Gos induced activation of caspase-3 and cytochrome c release from mitochondria, showing mitochondrial dysfunction pathway is operational during apoptosis. Further investigation revealed that phosphorylation of Bcl-2 at serine-70 was attenuated by Gos treatment, while protein levels were not affected. In addition, Mcl-1 was downregulated by Gos. Interestingly, phosphorylation of JAK2, STAT3, ERK1/2 and p38MAPK was inhibited by Gos-treatment, indicating that Gos globally suppressed interleukin-6 (IL-6) signals. Moreover, JAK2 inhibition mimicked the effect of Gos in OPM2 cells including Bcl-2 dephosphorylation and Mcl-1 downregulation. These results demonstrated that Gos induces apoptosis in MM cells not only through displacing BH3-only proteins from Bcl-2, but also through inhibiting IL-6 signaling, which leads to Bcl-2 dephosphorylation and Mcl-1 downregulation.

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“…It was initially used as an antifertility drug and subsequently as a cytotoxic agent [13,45]. There are two enantiomers of gossypol: (+)-gossypol and (−)-gossypol.…”

Section: Introductionmentioning

confidence: 99%