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Keywords:

  • resveratrol;
  • resveratrol metabolism;
  • free radicals;
  • antitumor effects;
  • polyhydroxyphenols;
  • melanoma;
  • ribonucleotide reductase

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Metabolism of resveratrol
  5. Analogs of resveratrol
  6. Biochemical effects of resveratrol and resveratrol analogs
  7. Structure–activity relationship
  8. In vivo effects of hexahydroxystilbene
  9. Conclusion
  10. Conflicts of interest
  11. References

Resveratrol is considered to have a number of beneficial effects. Recently, our group modified the molecule and synthesized a number of compounds with different biochemical effects. Polymethoxy and polyhydroxy derivatives of resveratrol were shown to inhibit tumor cell growth in various cell lines and inflammation pathways (cyclooxygenases activity), in part more effectively than resveratrol itself. One lead compound (hexahydroxystilbene, M8) turned out to be the most effective inhibitor of tumor cell growth and of cyclooxygenase 2 activity. M8 was then studied in two different human melanoma mouse models. This novel resveratrol analog was able to inhibit melanoma tumors in a primary tumor model alone and in combination with dacarbacine, an anticancer compound that is used for melanoma treatment. We also tested the development of lymph node metastasis in a second melanoma model and again M8 successfully inhibited the tumor as well as the size and weight of lymph node metastasis. Hydroxylated resveratrol analogs therefore represent a novel class of anticancer compounds and promising candidates for in vivo studies.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Metabolism of resveratrol
  5. Analogs of resveratrol
  6. Biochemical effects of resveratrol and resveratrol analogs
  7. Structure–activity relationship
  8. In vivo effects of hexahydroxystilbene
  9. Conclusion
  10. Conflicts of interest
  11. References

Resveratrol (3,4′,5-trihydroxy-trans-stilbene, Fig. 1) is considered to be the ingredient of red wine responsible for the so-called French paradox.1 Indeed, the incidence of heart infarction is 40% lower in France than in the rest of the Western world, despite similar demographics. One reason for this effect might be the drinking habits in France and the preventive effects of wine ingredients like alcohol and/or hydroxyphenolic compounds such as gallic acid or resveratrol. Resveratrol was identified to be one important ingredient of red wine. It is an excellent free radical scavenger with numerous beneficial effects including the prevention of blood vessel disease. For instance, platelet inhibition or inhibition of low density lipoprotein (LDL) cholesterol oxidation by resveratrol might be reasons for these beneficial effects. In addition to anti-inflammatory effects, resveratrol was identified as a chemopreventive agent against malignant transformation.2–4 Potter et al. identified polyhydroxy metabolites of resveratrol and speculated that the beneficial effects might also be caused by metabolites and intermediates.5 Our group has previously studied various other polyhydroxyphenols, such as didox and trimidox and their biochemical and cytotoxic effects, in various tumor cell systems and in animals, elucidating mechanisms responsible for the biochemical interactions of these compounds. Elford et al., who invented didox and trimidox (polyhydroxy-substituted benzohydroxamic acid derivates), have found that the number and position of hydroxyl groups on the phenol ring significantly influences the activity of the compounds.7,8 These findings were confirmed by our experiments, and we speculated that similar effects might be true for resveratrol and resveratrol analogs. Resveratrol is also a molecule consisting of hydroxyphenolic moieties and shares important biochemical targets with didox or trimidox. For instance, despite other biochemical effects it was shown that not only didox and trimidox but resveratrol is a highly active inhibitor of the enzyme ribonucleotide reductase (RR), a key enzyme of DNA synthesis in malignant cells.9 Inhibition of this enzyme can target tumor cells and cause inhibition of rapidly proliferating tumor cell growth, whereas non-malignant cells proliferate at a lower rate and do not need RR activity for survival. The enzyme needs a free tyrosyl radical for activity, and compounds with free radical scavenging activity can inhibit enzyme activity. This leads to the inhibition of the formation of deoxynucleoside triphosphates (dNTP) in tumor cells. As dNTPs are needed for DNA synthesis, inhibition of RR can cause growth arrest and apoptosis of tumor cells. Therefore, this enzyme is considered to be an excellent target for anticancer agents.

image

Figure 1. Structures of resveratrol, piceatannol, and hexahydroxystilbene (M8).

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Metabolism of resveratrol

  1. Top of page
  2. Abstract
  3. Introduction
  4. Metabolism of resveratrol
  5. Analogs of resveratrol
  6. Biochemical effects of resveratrol and resveratrol analogs
  7. Structure–activity relationship
  8. In vivo effects of hexahydroxystilbene
  9. Conclusion
  10. Conflicts of interest
  11. References

Several studies conducted on humans have reported a very low oral bioavailability based on extensive biotransformation. The metabolic pattern of resveratrol is complex; Boocock et al. identified two monosulfates, one disulfate, two monoglucuronides, and one glucuronide-sulfate in human plasma.10 In contrast, Burkon et al. identified seven metabolites, namely 3-sulfate, 3,4′-disulfate, 3,5-disulfate, 3-glucuronide, 4′-glucuronide, and two diglucuronides (Fig. 2).11 These discrepancies may be explained by a strong influence of applied dose on the metabolic profile of resveratrol. In vitro studies conducted by our lab using human intestinal Caco-2 cells and the isolated perfused rat liver showed that sulfation prevailed in the lower resveratrol concentrations, but when the applied dose was raised, sulfate formation dropped dramatically. As a consequence of the observed inhibition of resveratrol sulfation, conjugation with glucuronic acid was the main metabolic pathway in higher resveratrol concentrations.12,13

image

Figure 2. Major resveratrol metabolites identified in humans.

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Although extensively metabolized, many preclinical studies have already proved the anticancer activity of resveratrol in vivo, and several phase I/II clinical trials of oral resveratrol in cancer prevention and therapy are already on the way. This discrepancy between observed in vivo action and extensive biotransformation may be explained by enzymatic hydrolysis of the resveratrol conjugates in the tissue, enterohepatic recirculation after deconjugation in the gut, or possible biological activity of the metabolites themselves. Indeed, very recent data showed that resveratrol conjugates are biological active.10,14 Resveratrol-3-sulfate but not the 3-glucuronide exhibited biological activities known to be mediated by parent resveratrol: induction of quinone reductase 1, free radical scavenging, inhibition of cyclooxygenase 1 or 2 isoenzymes (COX-1/2), and inhibition of alpha-induced NF-κB activity or activation of SIRT1.15,16 Resveratrol-3-glucuronide, on the other hand, showed higher antioxidant activity than the parent compound itself.17 These recent studies indicate that the resveratrol conjugates may act through different molecular targets and therefore contribute in vivo to the diversity of health benefits previously attributed only to resveratrol itself.

Analogs of resveratrol

  1. Top of page
  2. Abstract
  3. Introduction
  4. Metabolism of resveratrol
  5. Analogs of resveratrol
  6. Biochemical effects of resveratrol and resveratrol analogs
  7. Structure–activity relationship
  8. In vivo effects of hexahydroxystilbene
  9. Conclusion
  10. Conflicts of interest
  11. References

In the attempt to improve the beneficial effects of resveratrol, including the induction of programmed cell death in tumor cells and the inhibition of inflammation by inhibiting cyclooxygenase activity, we synthesized a number of polyhydroxy and polymethoxy substituted analogs of resveratrol (Table 1).18 Cyclooxygenase is the enzyme responsible for prostaglandin synthesis from arachidonic acid. Two isoenzymes are known: COX-1 and COX-2. COX-1 is constitutively expressed and its inhibition is responsible for side effects of various anti-inflammatory compounds, and COX-2 inhibition is responsible for the anti-inflammatory and pain relieving effects. Resveratrol, like aspirin, inhibits both forms of cyclooxygenases. Looking for analogs of resveratrol that might exhibit COX-2 selectivity, a quantitative structure–activity relationship study was performed in order to identify various structural parameters of the molecules with inhibitory effects on COX-1 and COX-2 inhibition (Table 2).18

Table 1.  Structures of the resveratrol analogs 1–1218Thumbnail image of
Table 2.  Inhibitory effect of 1–12 and the reference compound celecoxib on COX-1 and COX-2 activity18
CompoundIC50 (μM)Selectivity index COX-1/COX-2
COX-1COX-2
  1. 7: resveratrol (3,5,4′-trihydroxy-trans-stilbene), 10: piceatannol (3,5,3′4′-tetrahydroxy-trans-stilbene, 12: M8 (3,4,5,3′,4′,5′-hexahydroxy-trans-stilbene).

 11.2281.6670.74
 29.0997.7971.17
 327.7831.57517.64
 42.8340.7963.56
 57.2470.51414.11
 611.3480.35531.97
 70.5350.9960.54
 82.0720.0453745.67
 90.009980.001715.83
104.7130.0113417.08
110.010270.001387.44
120.7480.00104719.23
Celecoxib19.0260.03482546.41

The methoxy derivatives were weak inhibitors of COX-1 with 2–55-fold higher IC50-values (the drug concentration that causes 50% inhibition of enzyme activity) than resveratrol.18 On the other hand, hydroxylated resveratrol analogs, especially tetra and pentahydroxystilbenes, were more potent inhibitors, with lower IC50-values.18 All hydroxylated analogs were more potent against COX-2 than resveratrol.18 Based on the IC50 values for COX-1 and COX-2, the relative IC50 ratios of COX-1/COX-2 were calculated. Resveratrol showed a weak COX-2 inhibition with a selectivity index (COX-1/COX-2) of 0.5.18 However, hexahydroxystilbene (M8) exhibited the highest selectivity index for COX-2 (selectivity index = 719); it was even more selective towards COX-2 than Celebrex® (selectivity index = 546), a commercially available highly selective COX-2 inhibitor.18 Methoxylated resveratrol analogs did not show any COX selectivity and inhibited COX-2 at much higher concentration than hydroxylated analogs.18 Very similar effects were seen when free radical scavenging capacities were investigated using our compounds.19

Free radical scavenging experiments with O2 (electron spin resonance) and 2,2-diphenyl-1-picrylhydrazyl (photometry) revealed that tetrahydroxystilbene and hexahydroxystilbene exerted a more than 6600-fold higher anti-radical activity than resveratrol.19 Furthermore, in HL-60 human leukemia cells, hydroxystilbenes with ortho-hydroxyl groups exhibited a more than three-fold higher cytotoxic activity than hydroxystilbenes with other substitution patterns.19 Oxidation of ortho-hydroxystilbenes in a microsomal model system resulted in the existence of ortho-semiquinones.19

Biochemical effects of resveratrol and resveratrol analogs

  1. Top of page
  2. Abstract
  3. Introduction
  4. Metabolism of resveratrol
  5. Analogs of resveratrol
  6. Biochemical effects of resveratrol and resveratrol analogs
  7. Structure–activity relationship
  8. In vivo effects of hexahydroxystilbene
  9. Conclusion
  10. Conflicts of interest
  11. References

Resveratrol was shown to cause a number of biochemical effects. Anti-inflammatory effects are described above. One important mechanism of action seems to be the free radical scavenging activity. Inhibition of RR was mentioned in the introduction; resveratrol causes an imbalance of dNTPs, which are precursors of DNA synthesis. In cancer cells, resveratrol can, for instance, induce apoptosis and downregulation of either NF-κB or Bcl2. All these biochemical effects play a role in the antineoplastic effects of resveratrol and resveratrol analogs.20–28 Our group first synthesized a number of analogs and then tested these compounds alone and in combination.18–28 One important drug combination is facilitating combination effects on dNTP synthesis, with the effects of a second group of antimetabolites to achieve additive and synergistic cytotoxic effects. First, we combined resveratrol and resveratrol analogs with cytosine arabinoside (Ara-C), which is converted to its triphosphate (Ara-CTP) for activity.23,27,28 Inhibition of RR depletes dNTP synthesis and decreases their pool sizes, with the consequence that more Ara-C can be phosphorylated to its active metabolite, which is then responsible for synergism.27 We could show that resveratrol, but also piceatannol, the monohydroxylated resveratrol metabolite as well as M8 were capable of enhancing the effects caused by Ara-C.23,27,28 Inhibition of DNA synthesis, such as other biochemical effects, also causes programmed cell death or apoptosis.

Hexahydroxystilbene (M8) was also shown to induce apoptosis at concentrations much lower than resveratrol (Fig. 3), which is in line with other experiments that showed the superior activity of M8.18,19

image

Figure 3. Induction of apoptosis by resveratrol and M8 in human HL-60 promyelocytic leukemia cells.

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Structure–activity relationship

  1. Top of page
  2. Abstract
  3. Introduction
  4. Metabolism of resveratrol
  5. Analogs of resveratrol
  6. Biochemical effects of resveratrol and resveratrol analogs
  7. Structure–activity relationship
  8. In vivo effects of hexahydroxystilbene
  9. Conclusion
  10. Conflicts of interest
  11. References

Structure–activity studies revealed that increasing the number of OH groups and their position (ortho) on the phenol ring could increase the free radical scavenging capacity of the compounds.19 We believe that the increased cytotoxicity of ortho-hydroxystilbenes is related to the presence of ortho-semiquinones formed during metabolism or autoxidation.19 In addition, cytotoxic activity could be enhanced, which was shown by lowering the IC50 values of the compounds active against a number of human tumor cell lines, including leukemia, prostate, colon, breast, and melanoma tumor cell lines.19–29 Polyhydroxy resveratrol derivatives, in particular the most effective hexahydroxy compound (M8), significantly inhibited the activity of the enzyme RR, which is considered to be a very important target for antitumor activity due to significantly increased enzyme activity in human tumor cells.28

We therefore selected M8 as lead compound for further investigations. M8 was used for in vivo experiments in human melanoma models.29,30

In vivo effects of hexahydroxystilbene

  1. Top of page
  2. Abstract
  3. Introduction
  4. Metabolism of resveratrol
  5. Analogs of resveratrol
  6. Biochemical effects of resveratrol and resveratrol analogs
  7. Structure–activity relationship
  8. In vivo effects of hexahydroxystilbene
  9. Conclusion
  10. Conflicts of interest
  11. References

As mentioned, M8 (hexahydroxystilbene) turned out to be the most effective resveratrol analog synthesized by our group.18,19 It provided the lowest IC50 values in tumor cell lines, showed highly selective cyclooxygenase 2 inhibitory activity at very low concentrations of the compound, and it was the most effective free radical scavenger out of a large group of polymethoxy and polyhydroxystilbene analogs.18,19 The compound was then examined in animal models. Two questions were addressed: is the compound toxic in vivo and is it proven to be active against in vivo tumors as well?29,30 We first investigated the single agent activity and mechanism of action of M8 in a human melanoma severe combined immunodeficiency (SCID) mouse xenotransplantation model.29 This tumor entity is still very difficult to treat and in the advanced stage only very few options for treatment are left. Therefore, there is a need for additional treatment options.

Mice suffering from palpable tumor disease after inoculation of human melanoma 518A2 cells were treated with i.p. doses of 2.5 and 5 mg/kg/day for a period of 4 weeks.29 Both doses were well tolerated and significantly reduced the weight of the primary tumor.29 Then, M8 was tested in combination with dacarbacine (DTIC), one of the few standard chemotherapeutic regimens used in human melanoma.29 After establishment of palpable tumors, the animals were treated with 2.5 mg/kg/day M8 for 14 days and, in addition, DTIC (80 mg/kg i.p.) was administered on days 4 and 6.29 The combination yielded highly significant synergistic effects.29 Three out of six animals treated with the combination were tumor free after 14 days of treatment; the other three animals displayed small residual tumors.29 These promising results prompted us to further investigate the effects of M8 in a melanoma metastasis tumor model in vivo.30 In a CB17 scid mouse model with M24met cells, the in vivo effects of M8 were studied. This model allows for the investigation of the effects on the primary tumor as well as the treatment effects on distant lymph node metastasis. Treatment of animals after the development of palpable tumors with 2.5 and 5 mg/kg M8 for 10 days caused a significant reduction of the primary tumor, which was accompanied by a reduction of Ki-67+ cells in the tumor.30 As the development of metastasis is a critical step for tumor spreading and disease progression, the effects of M8 on lymph-node metastasis were studied in this model. The above-mentioned treatment regimen was continued for another 10 days, and then lymph nodes were evaluated. Lymph nodes of the control group weighed 0.75 mg whereas treatment with 2.5 or 5 mg/kg M8 reduced weight significantly to 0.3 mg.30 These results were confirmed when lymph node volumes were calculated. The number of tumor cells in the lymph nodes could also be reduced significantly by ∼50% by treatment with M8.30 Inguinal stage of metastasis was reached in 56% of untreated animals, whereas none of the treated animals displayed inguinal tumor metastasis.30 We therefore conclude that treatment leads to a reduction of distant lymph node metastasis, which underlines that M8 might be a very promising approach for the treatment of human melanomas. Further beneficial effects might be seen with drug combinations using M8 together with conventional chemotherapeutic regimens.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Metabolism of resveratrol
  5. Analogs of resveratrol
  6. Biochemical effects of resveratrol and resveratrol analogs
  7. Structure–activity relationship
  8. In vivo effects of hexahydroxystilbene
  9. Conclusion
  10. Conflicts of interest
  11. References

We conclude that resveratrol, as well as polyhydroxy analogs of resveratrol, are able to alter various biochemical pathways, and thus they might be used not only as preventive agents against blood vessel disease but also in the treatment of inflammation and cancer.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Metabolism of resveratrol
  5. Analogs of resveratrol
  6. Biochemical effects of resveratrol and resveratrol analogs
  7. Structure–activity relationship
  8. In vivo effects of hexahydroxystilbene
  9. Conclusion
  10. Conflicts of interest
  11. References
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