- Email: [email protected]
(Pro-)vitamin D as treatment option for hedgehog-related malignancies
202 in levels of pro-inflammatory cytokines may also occur as a secondary and long-lasting reaction to a primary insult to dopaminergic neurons [3]. If neuroinflammation is not directly involved in the pathogenesis of PD, it may be related, at least partially, to the progression of the disease. Depressive disorders are extremely common in PD and may precede its motor signs by a period of 4–7 years [2], paralleling the onset of neurodegeneration. In addition, depression is frequently associated with immunological activation, especially of the innate immune system. Increased levels of TNF-a, IL-1-b, IL-6, acute phase proteins, and increased expression of chemokines and adhesion molecules have been frequently observed in peripheral blood and CSF of depressed patients [4]. Moreover, the administration of cytokine inducers or of recombinant cytokines, like TNF-a or IL-1-b, produces behavioral and psychological changes that mimics a condition known as ‘‘sickness behavior’’, which refers to a constellation of symptoms frequently seen in sick individuals during the course of an infection [4,5]. These neurovegetative symptoms of sickness, including malaise, lassitude, fatigue, aches, sleep disturbance, reduced appetitive behaviors, listlessness, social withdrawal, overlap frequently with depressive phenomenology. Nevertheless, besides developing these sickness symptoms, patients undergoing treatment for viral infections (e.g. hepatitis C) or cancer and receiving recombinant cytokines, specially interferon (IFN)c, develop typical depressive (cognitive and affective) symptoms in up to 50% of cases [4]. They include sadness, anhedonia and even suicidal ideation, which may be prevented by pretreatment with a selective serotonin reuptake inhibitor (SSRI) [5]. However, this kind of pretreatment has a minimal effect on symptoms more closely related to the sickness behavior, namely, the neurovegetative ones [5]. The interference of cytokines on serotonergic neurotransmission may explain changes in mood and the efficacy of the pretreat-
Correspondence ment with a SSRI. Anhedonia, fatigue, psychomotor retardation and other vegetative symptoms probably reflect a decrease in dopaminergic neurotransmission, as cytokines, such as IFN-c, may alter metabolic activity in the basal ganglia and worsen these symptoms [4,5]. Thus, immunological alteration may be a pivotal mechanism in both PD and its depressive symptoms, and pharmacological treatment with some cytokine antagonists and neurotrophic factors, for example, may be effective in hindering disease progression and ameliorating some depressive symptoms domains (e.g. fatigue, apathy, psychomotor retardation). This hypothesis raises relevant issues as it has important research and clinical implications.
References [1] Whitton PS. Inflammation as a causative factor in the aetiology of Parkinson’s disease. Br J Pharmacol 2007;150: 963–76. [2] Shiba M, Bower JH, Maraganore DM, et al. Anxiety disorders and depressive disorders preceding Parkinson’s disease: a case-control study. Mov Disord 2000;15:669–77. [3] Nagatsu T, Sawada M. Inflammatory process in Parkinson’s disease: role for cytokines. Curr Pharm Des 2005;11: 999–1016. [4] Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006;27:24–31. [5] Dantzer R. Cytokine, sickness behavior, and depression. Neurol Clin 2006;24:441–60.
Arthur Kummer * Antonio Lucio Teixeira Neuropsychiatric Branch, Department of Internal Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil * Tel.: +55 31 30241577. E-mail address: [email protected] (A. Kummer).
doi:10.1016/j.mehy.2007.08.002
(Pro-)vitamin D as treatment option for hedgehogrelated malignancies Very few effective treatment strategies are available for pancreatic cancer and other tumors of the proximal gastrointestinal (GI) tract (esophagus, stomach, duodenum). The relatively high incidence
(10 cases per 10,000 individuals for pancreatic cancer annually in Western countries) and lack of adequate treatment strategies call for novel therapeutic options [1]. Intriguingly, recent research
Correspondence efforts implicated an overactive hedgehog (Hh) pathway as being causative for most upper GI tract tumors [2]. The developmental Hh pathway is best known for its role in embryonic patterning, but is also pivotal in adult (patho)physiology [3]. Related to cancer biology, excessive Hh signaling has most extensively been characterized in pancreatic cancer. In normal pancreatic tissue, Hh is not expressed and no pathway activity is observed. In transformed pancreatic tissue, expression of Hh is induced, the pathway is subsequently activated, and severe metaplasia is observed [4,5]. An obvious candidate for combating abovementioned malignancies of the upper GI tract is the benchmark Hh pathway inhibitor cyclopamine. Cyclopamine is a plant alkaloid that antagonizes the activating receptor of the Hh pathway, i.e., smoothened [6]. Model systems (in vitro and in vivo) showed that cyclopamine very effectively inhibited the growth of those tumors dependent on an overactive Hh pathway. Clinical application was, however, rather inefficient and had severe side effects. Recently, (pro-)vitamin D has been identified as the naturally occurring inhibitor of the Hh pathway by targeting smoothened [7]. As (pro-)vitamin D, which is intrinsically safe even in high doses, is a more potent inhibitor of the Hh pathway than cyclopamine, we hypothesize that (pro-)vitamin D will prove an effective treatment strategy for malignancies dependent on an excessively active Hh pathway. In support of our hypothesis, several epidemiological observations indicate that sun exposure [8] or elevated vitamin D levels reduce GI cancer incidence and mortality [9]. In conclusion, (pro-)vitamin D seems a promising treatment strategy for Hh dependent malignancies of the GI tract. Experimental studies are, therefore, warranted to establish the efficiency of vitamin D in the treatment of these high malignant cancers.
References [1] Schneider G, Siveke JT, Eckel F, Schmid RM. Pancreatic cancer: basic and clinical aspects. Gastroenterology 2005;128:1606–25. doi:10.1016/j.mehy.2007.08.003
203 [2] Berman DM, Karhadkar SS, Maitra A, De Oca R Montes, Gerstenblith MR, Briggs K, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003;425:846–51. [3] Bijlsma MF, Peppelenbosch MP, Spek CA. Hedgehog morphogen in cardiovascular disease. Circulation 2006;114: 1985–91. [4] Morton JP, Mongeau ME, Klimstra DS, Morris JP, Lee YC, Kawaguchi Y, et al. Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci USA 2007;104:5103–8. [5] di Magliano M Pasca, Sekine S, Ermilov A, Ferris J, Dlugosz M, Hebrok M. Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Gene Develop 2006;20: 3161–73. [6] Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, et al. Effects of oncogenic mutations in smoothened and patched can be reversed by cyclopamine. Nature 2000;406: 1005–9. [7] Bijlsma MF, Spek CA, Zivkovic D, van de Water S, Rezaee F, Peppelenbosch MP. Repression of smoothened by patcheddependent (pro-)vitamin D3 secretion. PLoS Biol 2006;4: e232. [8] Tuohimaa P, Pukkala E, Scelo G, Olsen JH, Brewster DH, Hemminki K, et al. Does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancers: vitamin D as a possible explanation. Eur J Cancer 2007;43: 1701–12. [9] Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006;98:451–9.
Maarten F. Bijlsma Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands Tel.: +31 20 5667062 E-mail address: [email protected] Maikel P. Peppelenbosch Department of Cell Biology, University of Groningen, Groningen, The Netherlands C. Arnold Spek Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands
Correspondence ment with a SSRI. Anhedonia, fatigue, psychomotor retardation and other vegetative symptoms probably reflect a decrease in dopaminergic neurotransmission, as cytokines, such as IFN-c, may alter metabolic activity in the basal ganglia and worsen these symptoms [4,5]. Thus, immunological alteration may be a pivotal mechanism in both PD and its depressive symptoms, and pharmacological treatment with some cytokine antagonists and neurotrophic factors, for example, may be effective in hindering disease progression and ameliorating some depressive symptoms domains (e.g. fatigue, apathy, psychomotor retardation). This hypothesis raises relevant issues as it has important research and clinical implications.
References [1] Whitton PS. Inflammation as a causative factor in the aetiology of Parkinson’s disease. Br J Pharmacol 2007;150: 963–76. [2] Shiba M, Bower JH, Maraganore DM, et al. Anxiety disorders and depressive disorders preceding Parkinson’s disease: a case-control study. Mov Disord 2000;15:669–77. [3] Nagatsu T, Sawada M. Inflammatory process in Parkinson’s disease: role for cytokines. Curr Pharm Des 2005;11: 999–1016. [4] Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006;27:24–31. [5] Dantzer R. Cytokine, sickness behavior, and depression. Neurol Clin 2006;24:441–60.
Arthur Kummer * Antonio Lucio Teixeira Neuropsychiatric Branch, Department of Internal Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil * Tel.: +55 31 30241577. E-mail address: [email protected] (A. Kummer).
doi:10.1016/j.mehy.2007.08.002
(Pro-)vitamin D as treatment option for hedgehogrelated malignancies Very few effective treatment strategies are available for pancreatic cancer and other tumors of the proximal gastrointestinal (GI) tract (esophagus, stomach, duodenum). The relatively high incidence
(10 cases per 10,000 individuals for pancreatic cancer annually in Western countries) and lack of adequate treatment strategies call for novel therapeutic options [1]. Intriguingly, recent research
Correspondence efforts implicated an overactive hedgehog (Hh) pathway as being causative for most upper GI tract tumors [2]. The developmental Hh pathway is best known for its role in embryonic patterning, but is also pivotal in adult (patho)physiology [3]. Related to cancer biology, excessive Hh signaling has most extensively been characterized in pancreatic cancer. In normal pancreatic tissue, Hh is not expressed and no pathway activity is observed. In transformed pancreatic tissue, expression of Hh is induced, the pathway is subsequently activated, and severe metaplasia is observed [4,5]. An obvious candidate for combating abovementioned malignancies of the upper GI tract is the benchmark Hh pathway inhibitor cyclopamine. Cyclopamine is a plant alkaloid that antagonizes the activating receptor of the Hh pathway, i.e., smoothened [6]. Model systems (in vitro and in vivo) showed that cyclopamine very effectively inhibited the growth of those tumors dependent on an overactive Hh pathway. Clinical application was, however, rather inefficient and had severe side effects. Recently, (pro-)vitamin D has been identified as the naturally occurring inhibitor of the Hh pathway by targeting smoothened [7]. As (pro-)vitamin D, which is intrinsically safe even in high doses, is a more potent inhibitor of the Hh pathway than cyclopamine, we hypothesize that (pro-)vitamin D will prove an effective treatment strategy for malignancies dependent on an excessively active Hh pathway. In support of our hypothesis, several epidemiological observations indicate that sun exposure [8] or elevated vitamin D levels reduce GI cancer incidence and mortality [9]. In conclusion, (pro-)vitamin D seems a promising treatment strategy for Hh dependent malignancies of the GI tract. Experimental studies are, therefore, warranted to establish the efficiency of vitamin D in the treatment of these high malignant cancers.
References [1] Schneider G, Siveke JT, Eckel F, Schmid RM. Pancreatic cancer: basic and clinical aspects. Gastroenterology 2005;128:1606–25. doi:10.1016/j.mehy.2007.08.003
203 [2] Berman DM, Karhadkar SS, Maitra A, De Oca R Montes, Gerstenblith MR, Briggs K, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003;425:846–51. [3] Bijlsma MF, Peppelenbosch MP, Spek CA. Hedgehog morphogen in cardiovascular disease. Circulation 2006;114: 1985–91. [4] Morton JP, Mongeau ME, Klimstra DS, Morris JP, Lee YC, Kawaguchi Y, et al. Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci USA 2007;104:5103–8. [5] di Magliano M Pasca, Sekine S, Ermilov A, Ferris J, Dlugosz M, Hebrok M. Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Gene Develop 2006;20: 3161–73. [6] Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, et al. Effects of oncogenic mutations in smoothened and patched can be reversed by cyclopamine. Nature 2000;406: 1005–9. [7] Bijlsma MF, Spek CA, Zivkovic D, van de Water S, Rezaee F, Peppelenbosch MP. Repression of smoothened by patcheddependent (pro-)vitamin D3 secretion. PLoS Biol 2006;4: e232. [8] Tuohimaa P, Pukkala E, Scelo G, Olsen JH, Brewster DH, Hemminki K, et al. Does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancers: vitamin D as a possible explanation. Eur J Cancer 2007;43: 1701–12. [9] Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006;98:451–9.
Maarten F. Bijlsma Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands Tel.: +31 20 5667062 E-mail address: [email protected] Maikel P. Peppelenbosch Department of Cell Biology, University of Groningen, Groningen, The Netherlands C. Arnold Spek Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands