- Email: [email protected]
Herbal medicine, cancer prevention and cyclooxygenase 2 inhibition
Update
218
TRENDS in Pharmacological Sciences
Taken together, these reports demonstrate that preclinical disease models can be manipulated by the delivery of biologically active proteins that have been evolutionarily selected to perform specific functions. Although these findings are exciting, several issues, including pharmacokinetics and potential immunogenicity, require further analysis before clinical trials can be undertaken. In addition, during ischemia it remains unclear if apoptosis is initiated by oxygen deprivation, alteration of glucose levels, static pressure changes and/or DNA damage. Consequently, it might be detrimental to preserve the function of cells harboring DNA damage by inhibiting apoptosis after a stroke. Concluding remarks Delivery of protein therapeutics using transduction technology offers a new and exciting strategy to treat stroke. This technology allows efficient delivery into a variety of different cells and tissues in a rapid, concentration-dependent manner. Moreover, this novel technique for protein delivery appears to circumvent many problems associated with DNA and drug-based techniques. Delivery of anti-apoptotic proteins could also afford new exciting opportunities in the treatment of other neurological disorders in addition to applications in preventing cell death during organ transplantation. Although the recent preclinical studies present compelling data on the utility of anti-apoptotic proteins via transduction in disease models, we will not know the true potential that this methodology
Vol.24 No.5 May 2003
affords for treating human disease until we have outcomes from future clinical trials. Acknowledgements S.F.D. is supported by the Howard Hughes Medical Institute and NIH.
References 1 Dirnagl, U. et al. (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22, 391 – 397 2 Grotta, J. (2002) Neuroprotection is unlikely to be effective in humans using current trial designs. Stroke 33, 306– 307 3 Graham, S.H. and Chen, J. (2001) Programmed cell death in cerebral ischemia. J. Cereb. Blood Flow Metab. 21, 99– 109 4 Adams, J.M. and Cory, S. (2001) Life-or-death decisions by the Bcl-2 protein family. Trends Biochem. Sci. 26, 61 – 66 5 Asoh, S. et al. (2002) Protection against ischemic brain injury by protein therapeutics. Proc. Natl. Acad. Sci. U. S. A. 99, 17107 – 17112 6 Kilic, E. et al. (2002) Intravenous TAT– Bcl-Xl is protective after middle cerebral artery occlusion in mice. Ann. Neurol. 52, 617 – 622 7 Cao, G. et al. (2002) In vivo delivery of a Bcl-xL fusion protein containing the TAT protein transduction domain protects against ischemic brain injury and neuronal apoptosis. J. Neurosci. 22, 5423– 5431 8 Dietz, G.P. et al. (2002) Inhibition of neuronal apoptosis in vitro and in vivo using TAT-mediated protein transduction. Mol. Cell. Neurosci. 21, 29 – 37 9 Wadia, J.S. and Dowdy, S.F. (2002) Protein transduction technology. Curr. Opin. Biotechnol. 13, 52 – 56 10 Schwarze, S.R. et al. (1999) In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285, 1569 – 1572 0165-6147/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0165-6147(03)00074-9
| Letters
Herbal medicine, cancer prevention and cyclooxygenase 2 inhibition Angelo A. Izzo and Francesco Capasso Department of Experimental Pharmacology, University of Naples Federico II, via D Montesano 49, 80131 Naples, Italy
In their recent TiPS article [1], Subbaramaiah and Dannenberg highlighted the possibility of employing selective cyclooxygenase 2 (COX-2) inhibitors in cancer prevention. Here, we wish to draw attention to several herbal medicines, namely green tea, ginseng and Allium vegetables (i.e. garlic and onion), that, on the basis of epidemiological studies, have shown promising signs of possessing chemopreventive activity [2]. An ability to inhibit COX-2 activity is a common feature of the active ingredients in these herbs. Green tea (Camellia sinensis leaves), which is consumed widely across eastern Asia, is a unique cancer preventive medicine with two distinct uses – as a beverage and as a drug. Its preparation differs from that of black tea because its freshly picked leaves are heated immediately. This destroys the enzymes responsible for breaking down Corresponding author: Angelo A. Izzo ([email protected]). http://tips.trends.com
the colour pigments in the leaves and allows the tea to maintain its green colour during the subsequent rolling and drying processes [2]. Inhibition of tumorigenesis by green tea has been demonstrated in animal models in different organ sites such as the skin, lung, oral cavity, oesophagus, stomach, small intestine, colon, pancreas and mammary gland. Mechanisms proposed to underlie the inhibition of carcinogenesis by green tea include: (1) the modulation of signal transduction pathways that lead to the inhibition of cell proliferation and transformation; (2) the induction of apoptosis of pre-neoplastic and neoplastic cells; (3) the inhibition of tumour invasion and angiogenesis; and (4) the inhibition of COX-2 activity [3]. Consistently, green tea polyphenols have been shown to inhibit COX-2 activity in human colon tumour tissues [4]. Furthermore, epidemiological studies have shown that green tea consumption (5 g green tea leaves, daily) prevented oesophageal cancer, but that gastric cancer was not
Update
TRENDS in Pharmacological Sciences
prevented by the consumption of five or more cups of green tea per day (equivalent to 1.25 g green tea leaves) [5]. In the USA, a Phase II clinical trial of green tea as a cancer preventive is anticipated. Ginseng (Panax ginseng roots) is an ancient Chinese medicine employed as a ‘cure-all’. Ginseng is chemopreventive in a variety of tumour models, including the azoxymethane model of colon cancer in which COX-2 is expressed [6]. The mechanisms of this chemopreventive action are yet to be elucidated but some ginsenosides (the active ingredients of ginseng) have been shown to inhibit COX-2 in mouse skin [7]. Published results from a cohort and two case-control studies in South Korea suggest that ginseng ingestion might reduce the risk of several types of cancer. Notably, in the cohort study, 4634 subjects were assessed by questionnaire about their ginseng intake. During the five years of follow-up, 137 cases of cancer occurred. People who regularly consumed ginseng had a lower risk of contracting cancer than those who did not consume ginseng [6]. . Garlic (Allium sativum bulb) and onion (Allium cepa bulb) are used for both dietary and medicinal purposes. Site-specific case-control studies and cohort studies suggest a preventive effect of Allium vegetable consumption against stomach, colorectal and prostate cancer, although evidence for a protective effect against cancer at other sites, including the breast, is still lacking [8]. It is noteworthy that a population-based, case-control study (n ¼ 238 subjects with prostate cancer) showed that men in the category of highest intake of total Allium vegetables (. 10 g day21) had a statistically significant lower risk of contracting prostate cancer than did those in the category of lowest intake (, 2.2 g day21) [9]. The protective effect of these herbs appears to be related to the presence of organosulfurous compounds that inhibit carcinogenesis in the fore-stomach, oesophagus, colon, mammary gland and lung of experimental animals. Allium derivatives regulate immune function and
Vol.24 No.5 May 2003
219
inflammation, in addition to cellular proliferation. In particular, the organosulfurous compound ajoene inhibited COX-2 activity in macrophages [10]. In summary, promising, although not compelling, data from clinical studies suggest that some herbal medicines might contribute to cancer prevention. Experimental studies indicate a possible link between COX-2 inhibition and cancer inhibition mediated by active ingredients in some herbs. The available evidence warrants further research into the possible role of herbal medicines in the prevention of human cancer and carcinogenesis. References 1 Subbaramaiah, K. and Dannenberg, A.J. (2003) Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol. Sci. 24, 96– 102 2 Capasso, F. et al. (2003) Phytotherapy. A Quick Reference of Herbal Medicine, Springer-Verlag 3 Yang, C.S. et al. (2002) Inhibition of carcinogenesis by tea. Annu. Rev. Pharmacol. Toxicol. 42, 25 – 54 4 Hong, J. et al. (2001) Effects of purified green and black tea polyphenols on cyclooxygenase- and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues. Biochem. Pharmacol. 62, 1175 – 1183 5 Fujiki, H. et al. (2002) Green tea: cancer preventive beverage and/or drug. Cancer Lett. 188, 9 – 13 6 Yun, T.K. (2001) Panax ginseng – a non-organ-specific cancer preventive? Lancet Oncol. 2, 49 – 55 7 Surh, Y.J. et al. (2002) Effects of selected ginsenosides on phorbol esterinduced expression of cyclooxygenase-2 and activation of NF-kB and ERK1/2 in mouse skin. Ann. New York Acad. Sci. 973, 396– 401 8 Fleischauer, A.T. and Arab, L. (2001) Garlic and cancer: a critical review of the epidemiologic literature. J. Nutr. 131, 1032S – 1040S 9 Hsing, A.W. et al. (2002) Allium vegetables and risk of prostate cancer: a population-based study. J. Natl. Cancer Inst. 94, 1648– 1651 10 Dirsch, V.M. and Vollmar, A.M. (2001) Ajoene, a natural product with non-steroidal anti-inflammatory drug (NSAID)-like properties? Biochem. Pharmacol. 61, 587 – 593 0165-6147/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0165-6147(03)00070-1
Investigator bias and false positive findings in medical research Edzard Ernst and Peter H. Canter Complementary Medicine, Peninsula Medical School, Universities of Exeter & Plymouth, 25 Victoria Park Road, Exeter EX2 4NT, UK
Bias is ubiquitous, and medical research is no exception. Indeed, a recently published list included 45 different types of bias in medical research [1]. However, investigator bias, which we define as bias resulting from a conflict of interest arising from passionate beliefs held by the investigators, was not among them. Although rarely discussed, such a conflict requires declaration [2]. Here,
Corresponding author: Edzard Ernst ([email protected]). http://tips.trends.com
we will outline how investigator bias can influence all stages of a research project. From the very outset, investigator bias can influence the general attitude towards a research project. Research is at its best when it tests (or, more precisely, falsifies) hypotheses. The biased researcher, however, has preconceived ideas and is likely to approach a project to ‘prove’ a point. For example, a researcher who is convinced of a particular treatment or, worse, has a vested interest in it, might misuse science to demonstrate the efficacy of his
218
TRENDS in Pharmacological Sciences
Taken together, these reports demonstrate that preclinical disease models can be manipulated by the delivery of biologically active proteins that have been evolutionarily selected to perform specific functions. Although these findings are exciting, several issues, including pharmacokinetics and potential immunogenicity, require further analysis before clinical trials can be undertaken. In addition, during ischemia it remains unclear if apoptosis is initiated by oxygen deprivation, alteration of glucose levels, static pressure changes and/or DNA damage. Consequently, it might be detrimental to preserve the function of cells harboring DNA damage by inhibiting apoptosis after a stroke. Concluding remarks Delivery of protein therapeutics using transduction technology offers a new and exciting strategy to treat stroke. This technology allows efficient delivery into a variety of different cells and tissues in a rapid, concentration-dependent manner. Moreover, this novel technique for protein delivery appears to circumvent many problems associated with DNA and drug-based techniques. Delivery of anti-apoptotic proteins could also afford new exciting opportunities in the treatment of other neurological disorders in addition to applications in preventing cell death during organ transplantation. Although the recent preclinical studies present compelling data on the utility of anti-apoptotic proteins via transduction in disease models, we will not know the true potential that this methodology
Vol.24 No.5 May 2003
affords for treating human disease until we have outcomes from future clinical trials. Acknowledgements S.F.D. is supported by the Howard Hughes Medical Institute and NIH.
References 1 Dirnagl, U. et al. (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22, 391 – 397 2 Grotta, J. (2002) Neuroprotection is unlikely to be effective in humans using current trial designs. Stroke 33, 306– 307 3 Graham, S.H. and Chen, J. (2001) Programmed cell death in cerebral ischemia. J. Cereb. Blood Flow Metab. 21, 99– 109 4 Adams, J.M. and Cory, S. (2001) Life-or-death decisions by the Bcl-2 protein family. Trends Biochem. Sci. 26, 61 – 66 5 Asoh, S. et al. (2002) Protection against ischemic brain injury by protein therapeutics. Proc. Natl. Acad. Sci. U. S. A. 99, 17107 – 17112 6 Kilic, E. et al. (2002) Intravenous TAT– Bcl-Xl is protective after middle cerebral artery occlusion in mice. Ann. Neurol. 52, 617 – 622 7 Cao, G. et al. (2002) In vivo delivery of a Bcl-xL fusion protein containing the TAT protein transduction domain protects against ischemic brain injury and neuronal apoptosis. J. Neurosci. 22, 5423– 5431 8 Dietz, G.P. et al. (2002) Inhibition of neuronal apoptosis in vitro and in vivo using TAT-mediated protein transduction. Mol. Cell. Neurosci. 21, 29 – 37 9 Wadia, J.S. and Dowdy, S.F. (2002) Protein transduction technology. Curr. Opin. Biotechnol. 13, 52 – 56 10 Schwarze, S.R. et al. (1999) In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285, 1569 – 1572 0165-6147/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0165-6147(03)00074-9
| Letters
Herbal medicine, cancer prevention and cyclooxygenase 2 inhibition Angelo A. Izzo and Francesco Capasso Department of Experimental Pharmacology, University of Naples Federico II, via D Montesano 49, 80131 Naples, Italy
In their recent TiPS article [1], Subbaramaiah and Dannenberg highlighted the possibility of employing selective cyclooxygenase 2 (COX-2) inhibitors in cancer prevention. Here, we wish to draw attention to several herbal medicines, namely green tea, ginseng and Allium vegetables (i.e. garlic and onion), that, on the basis of epidemiological studies, have shown promising signs of possessing chemopreventive activity [2]. An ability to inhibit COX-2 activity is a common feature of the active ingredients in these herbs. Green tea (Camellia sinensis leaves), which is consumed widely across eastern Asia, is a unique cancer preventive medicine with two distinct uses – as a beverage and as a drug. Its preparation differs from that of black tea because its freshly picked leaves are heated immediately. This destroys the enzymes responsible for breaking down Corresponding author: Angelo A. Izzo ([email protected]). http://tips.trends.com
the colour pigments in the leaves and allows the tea to maintain its green colour during the subsequent rolling and drying processes [2]. Inhibition of tumorigenesis by green tea has been demonstrated in animal models in different organ sites such as the skin, lung, oral cavity, oesophagus, stomach, small intestine, colon, pancreas and mammary gland. Mechanisms proposed to underlie the inhibition of carcinogenesis by green tea include: (1) the modulation of signal transduction pathways that lead to the inhibition of cell proliferation and transformation; (2) the induction of apoptosis of pre-neoplastic and neoplastic cells; (3) the inhibition of tumour invasion and angiogenesis; and (4) the inhibition of COX-2 activity [3]. Consistently, green tea polyphenols have been shown to inhibit COX-2 activity in human colon tumour tissues [4]. Furthermore, epidemiological studies have shown that green tea consumption (5 g green tea leaves, daily) prevented oesophageal cancer, but that gastric cancer was not
Update
TRENDS in Pharmacological Sciences
prevented by the consumption of five or more cups of green tea per day (equivalent to 1.25 g green tea leaves) [5]. In the USA, a Phase II clinical trial of green tea as a cancer preventive is anticipated. Ginseng (Panax ginseng roots) is an ancient Chinese medicine employed as a ‘cure-all’. Ginseng is chemopreventive in a variety of tumour models, including the azoxymethane model of colon cancer in which COX-2 is expressed [6]. The mechanisms of this chemopreventive action are yet to be elucidated but some ginsenosides (the active ingredients of ginseng) have been shown to inhibit COX-2 in mouse skin [7]. Published results from a cohort and two case-control studies in South Korea suggest that ginseng ingestion might reduce the risk of several types of cancer. Notably, in the cohort study, 4634 subjects were assessed by questionnaire about their ginseng intake. During the five years of follow-up, 137 cases of cancer occurred. People who regularly consumed ginseng had a lower risk of contracting cancer than those who did not consume ginseng [6]. . Garlic (Allium sativum bulb) and onion (Allium cepa bulb) are used for both dietary and medicinal purposes. Site-specific case-control studies and cohort studies suggest a preventive effect of Allium vegetable consumption against stomach, colorectal and prostate cancer, although evidence for a protective effect against cancer at other sites, including the breast, is still lacking [8]. It is noteworthy that a population-based, case-control study (n ¼ 238 subjects with prostate cancer) showed that men in the category of highest intake of total Allium vegetables (. 10 g day21) had a statistically significant lower risk of contracting prostate cancer than did those in the category of lowest intake (, 2.2 g day21) [9]. The protective effect of these herbs appears to be related to the presence of organosulfurous compounds that inhibit carcinogenesis in the fore-stomach, oesophagus, colon, mammary gland and lung of experimental animals. Allium derivatives regulate immune function and
Vol.24 No.5 May 2003
219
inflammation, in addition to cellular proliferation. In particular, the organosulfurous compound ajoene inhibited COX-2 activity in macrophages [10]. In summary, promising, although not compelling, data from clinical studies suggest that some herbal medicines might contribute to cancer prevention. Experimental studies indicate a possible link between COX-2 inhibition and cancer inhibition mediated by active ingredients in some herbs. The available evidence warrants further research into the possible role of herbal medicines in the prevention of human cancer and carcinogenesis. References 1 Subbaramaiah, K. and Dannenberg, A.J. (2003) Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol. Sci. 24, 96– 102 2 Capasso, F. et al. (2003) Phytotherapy. A Quick Reference of Herbal Medicine, Springer-Verlag 3 Yang, C.S. et al. (2002) Inhibition of carcinogenesis by tea. Annu. Rev. Pharmacol. Toxicol. 42, 25 – 54 4 Hong, J. et al. (2001) Effects of purified green and black tea polyphenols on cyclooxygenase- and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues. Biochem. Pharmacol. 62, 1175 – 1183 5 Fujiki, H. et al. (2002) Green tea: cancer preventive beverage and/or drug. Cancer Lett. 188, 9 – 13 6 Yun, T.K. (2001) Panax ginseng – a non-organ-specific cancer preventive? Lancet Oncol. 2, 49 – 55 7 Surh, Y.J. et al. (2002) Effects of selected ginsenosides on phorbol esterinduced expression of cyclooxygenase-2 and activation of NF-kB and ERK1/2 in mouse skin. Ann. New York Acad. Sci. 973, 396– 401 8 Fleischauer, A.T. and Arab, L. (2001) Garlic and cancer: a critical review of the epidemiologic literature. J. Nutr. 131, 1032S – 1040S 9 Hsing, A.W. et al. (2002) Allium vegetables and risk of prostate cancer: a population-based study. J. Natl. Cancer Inst. 94, 1648– 1651 10 Dirsch, V.M. and Vollmar, A.M. (2001) Ajoene, a natural product with non-steroidal anti-inflammatory drug (NSAID)-like properties? Biochem. Pharmacol. 61, 587 – 593 0165-6147/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0165-6147(03)00070-1
Investigator bias and false positive findings in medical research Edzard Ernst and Peter H. Canter Complementary Medicine, Peninsula Medical School, Universities of Exeter & Plymouth, 25 Victoria Park Road, Exeter EX2 4NT, UK
Bias is ubiquitous, and medical research is no exception. Indeed, a recently published list included 45 different types of bias in medical research [1]. However, investigator bias, which we define as bias resulting from a conflict of interest arising from passionate beliefs held by the investigators, was not among them. Although rarely discussed, such a conflict requires declaration [2]. Here,
Corresponding author: Edzard Ernst ([email protected]). http://tips.trends.com
we will outline how investigator bias can influence all stages of a research project. From the very outset, investigator bias can influence the general attitude towards a research project. Research is at its best when it tests (or, more precisely, falsifies) hypotheses. The biased researcher, however, has preconceived ideas and is likely to approach a project to ‘prove’ a point. For example, a researcher who is convinced of a particular treatment or, worse, has a vested interest in it, might misuse science to demonstrate the efficacy of his