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Curcumin as an Adjunct Drug for Infectious Diseases
TIPS 1282 No. of Pages 3
Forum
Curcumin as an Adjunct Drug for Infectious Diseases Govindarajan Padmanaban1,* and Pundi N Rangarajan1 Curcumin, by virtue of its ability to function as an immunomodulator, has the potential to serve as an adjunct drug to treat infectious diseases and provide long-term protection. The current need is to establish clinical trials with curcumin as an adjunct drug against specific infectious diseases. Millions of those living in poverty are disproportionately afflicted by infectious diseases, with prolonged illness, life-long disability, and mortality accounting for almost nine million deaths annually. In addition to HIV, TB, and malaria, neglected tropical diseases (NTDs), comprising 17 bacterial[1_TD$IF], protozoan, and viral infections (e.g., leishmaniasis, African trypanosomiasis, Chagas, cysticercosis, dengue, rabies, etc.) account for around 40% of the global disease burden [1,2]. While strategies are debated in terms of public health measures to prevent and contain infectious diseases, major issues at the therapeutic level are the exorbitant treatment costs of current treatments, the increasing challenges posed by drug and/ or antibiotic resistance, and the consequent need to discover new, more affordable, drugs. It is in this context that the use of dietary curcumin, an affordable, nontoxic, adjunct drug with no history of drug resistance, to treat infectious diseases needs to be seriously investigated.
Cytokines
Enzymes
Transcripon factors
Cancers Parasic
Hepac and biliary
Adhesion molecules
Inflammatory
Bacterial Micro RNAs
Cell cycle proteins
Curcumin Neuro degenerave
Viral
Cardio vascular
Renal Protein kinases
Metabolic
Apoptoc machinery
Growth factors
Receptors
Figure 1. Snapshot of Diseases that Could be Treated with Curcumin (Blue Circles) and its Molecular Targets (Black Circles).
number of diseases [3], with an equally large number of identified molecular targets (Figure 1) [4]. It has also been reported to be effective against pathogens causing infectious diseases [5]. Most of the clinical trials (more than 100, either completed or ongoing) focus on cancers and systemic disorders, and have trended toward a general positive outcome; however, these results need to be confirmed with well-planned, randomized designs. By contrast, there are few examples of clinical trials investigating curcumin as a treatment for infectious diseases, although many preclinical studies have indicated significant beneficial effects (see below).
curcumin would be to undertake clinical trials with select infectious diseases in which it would be possible to use curcumin as an adjunct drug to standard therapy and for which the treatment duration is short. With the development of resistance to antibiotics in general, curcumin may hold promise to ameliorate drug resistance, since it tends to decrease the toxicity and dose of the primary drug [3]. While most anti-infectives kill the pathogen by inhibiting fundamental molecular processes relating to its growth and survival, curcumin may offer protection through immunomodulation of the host response rather than by a direct killing effect on the pathogen. Thus, specific Curcumin as an Antimicrobial infectious diseases of major concern Agent where the potential for the use of curcumin Curcumin, which is extracted from tur- What is the Best Way Forward? meric, is a well-known enigmatic molecule We suggest that the best approach to has been demonstrated can be used to with potential health benefits in a large investigating the drug potential of study its efficacy in human clinical trials.
Trends in Pharmacological Sciences, Month Year, Vol. xx, No. yy
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TIPS 1282 No. of Pages 3
Potential Diseases for Curcumin Adjunct Therapy Helicobacter[2_TD$IF] pylori[3_TD$IF] is a common human pathogen that infects half of the population of the world, and, in some cases, is responsible for inflammation of the gastric mucosa that leads to gastric cancer. Its incidence is higher in the developing world than elsewhere due to socioeconomic factors. Development of antibiotic resistance is also an issue. In a recent study in the mouse model of H. pylori infection, curcumin was shown to counteract all the inflammatory parameters based on cytokine, chemokine, and Toll-like receptor (TLR) PCR assays, and the C13 urea-breath test [6]. An encouraging development was the organization of a human clinical trial with 150 patients to study the impact of the addition of curcumin to a 10-day standard triple therapy (proton-pump inhibitor, clarithromycin, and amoxicillin) [7]. This is on the basis that curcumin may show synergistic effects, when used in combination therapy. Methicillin-resistant Staphylococcus aureus (MRSA) has been associated with considerable morbidity and mortality and is a major public health issue worldwide. The rapid spread of antibiotic resistance is posing a serious challenge to its treatment. MRSA has established itself as a common nosocomial pathogen and is being increasingly implicated in both healthcare- and community-associated infections [8]. Curcumin has been shown to significantly decrease the minimal inhibitory concentration of the antibiotics oxacillin, ampicillin, ciprofloxacin, and norfloxacin, which are currently used against MRSA. Curcumin–oxacillin treatment was shown to reduce bacterial counts below detectable limits within 24 h [9]. However, further studies are needed to determine the efficacy of this combination therapy in vivo. The combination of curcumin with the antimalarial drug arteether is effective in killing the murine malaria parasite, Plasmodium berghei. It is also effective in
2
preventing parasite recrudescence by inhibiting the inflammatory T helper type 1 (Th1) response and promoting the antiinflammatory Th2 response [10]. It is able to prevent sequestration of parasiteinfected red blood cells in the brain and the onset of neurological symptoms in experimental cerebral malaria (ECM). In particular, curcumin shows synergism with arteether in curing ECM after the onset of symptoms [11]. Mortality in cerebral malaria is as high as 15–25%, despite the use of primary treatment with artemisinin derivatives. Chagas disease, which is caused by infection with Trypanosoma cruzi, infects six– seven million people worldwide, mostly in Latin America, although the disease is now spreading to other continents. It can lead to cardiac and gastrointestinal complications, resulting in mortality and physical disabilities. The disease is curable with benznidazole and nifurtimox, when treated soon after infection, with efficacy decreasing the longer the infection lasts. Curcumin treatment has been shown to cause a significant reduction in macrophage infiltration and inflammation in both the heart and liver. Curcumin-treated infected mice displayed a 100% survival rate in contrast to the 60% survival rate commonly observed in untreated infected mice [12]. Therefore, it would be useful to test the efficacy of combination therapy with curcumin.
Concluding Remarks
Thus, curcumin as an adjunct drug would provide long-term benefits through immunomodulation, and this is especially relevant in cases where a vaccine is not available. As a start, specific examples where proof of principle exists for the efficacy of curcumin in vivo can be taken up for evaluation in the presence and absence of the primary drug in use. It is proposed that philanthropic organizations, such as the Bill & Melinda Gates Foundation, could promote preclinical and efficacy trials for assessing the benefits of curcumin and formulations that can enhance bioavailability, if considered necessary, as an adjunct drug in the examples discussed, where a substantial population in the developing countries is at risk. Since the treatments are for a relatively shorter period for infectious disease (relative to cancer, for example) and the end points are clearly quantifiable, this would help to establish curcumin as a viable, affordable adjunct drug to treat specific infectious diseases. An advantage to the study of infectious diseases is that the beneficial effects can be assessed in clear terms, unlike cancers, where more often the patient benefits can remain blurred by the long duration of treatment required and the complex nature of the disease. Such an approach would establish the use of curcumin backed by hard-core scientific and clinical evidence that may pave the way for its wider use. It might be that the use of curcumin as an adjunct drug rather than as a primary anticancer drug would elicit a credible beneficial response.
It would appear that curcumin may have beneficial effects in treating infectious diseases, despite issues with poor bioavail- Acknowledgments ability and rapid metabolism. It might be The research on the use of curcumin to treat experithat curcumin modulates immune mem- mental malaria in the authors’ laboratory was carried ory in the presence of either the pathogen out in a Centre of Excellence project supported by the Department of Biotechnology, Government of India. or antigen(s) from the pathogen generated G.P. is a senior scientist of the Indian National Science by the direct killing effect of the primary Academy. drug. In certain instances, it is able to aid the immune response and prevent fresh 1Department of Biochemistry, Indian Institute of Science, infection as well as to offer protection and Bangalore 560012, India cure long after the primary drug has dis- *Correspondence: [email protected] appeared from the system, as shown in (G. Padmanaban). the case of experimental malaria [10,11]. http://dx.doi.org/10.1016/j.tips.2015.09.007
Trends in Pharmacological Sciences, Month Year, Vol. xx, No. yy
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References 1. WHO (2012) Global Report for Research on Infectious Disease of Poverty, WHO 2. Bhutta, Z.A. et al. (2014) Global burden, distribution and interventions for infectious diseases of poverty. Infect. Dis. Poverty 3, 21 3. Gupta, S. et al. (2013) Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 15, 195–218 4. Shishodia, S. (2013) Molecular mechanisms of curcumin action: gene expression. Biofactors 39, 37–55 5. Moghadamtousi, S.Z. et al. (2014) A review on antibacterial, antiviral and antifungal activity of curcumin. BioMed Res. Int. 2014, 186864
6. Santos, A.M. et al. (2015) Curcumin inhibits gastric inflammation induced by Helicobacter pylori infection in a mouse model. Nutrients 7, 306–320 7. Rachel, G.B. Rabin Medical Center. The impact of addition of curcumin in 10 days triple therapy, on the eradication rate of Helicobacter pylori infection (CurHP). NCT02018328 8. Ray, P. et al. (2011) Methicillin-resistant Staphylococcus aureus in developed and developing countries: implications and solutions. Regional Health Forum 15, 74–82 9. Mun, S.H. et al. (2013) Synergistic antibacterial effect of curcumin against methicillin-resistant Staphylococcus aureus. Phytomedicine 20, 714–718
10. Vathsala, P.G. et al. (2012) Curcumin-arteether combination therapy of Plasmodium berghei-infected mice prevents recrudescence through immunomodulation. PLoS ONE 7, e29442 11. Dende, C. et al. (2015) Simultaneously targeting inflammatory response and parasite sequestration in brain to treat experimental cerebral malaria. Sci. Rep. 5, e12671 12. Nagajyothi, F. et al. (2012) Curcumin treatment provides protection against Trypanosoma cruzi infection. Parasitol. Res. 110, 2491–2499
Trends in Pharmacological Sciences, Month Year, Vol. xx, No. yy
3
Forum
Curcumin as an Adjunct Drug for Infectious Diseases Govindarajan Padmanaban1,* and Pundi N Rangarajan1 Curcumin, by virtue of its ability to function as an immunomodulator, has the potential to serve as an adjunct drug to treat infectious diseases and provide long-term protection. The current need is to establish clinical trials with curcumin as an adjunct drug against specific infectious diseases. Millions of those living in poverty are disproportionately afflicted by infectious diseases, with prolonged illness, life-long disability, and mortality accounting for almost nine million deaths annually. In addition to HIV, TB, and malaria, neglected tropical diseases (NTDs), comprising 17 bacterial[1_TD$IF], protozoan, and viral infections (e.g., leishmaniasis, African trypanosomiasis, Chagas, cysticercosis, dengue, rabies, etc.) account for around 40% of the global disease burden [1,2]. While strategies are debated in terms of public health measures to prevent and contain infectious diseases, major issues at the therapeutic level are the exorbitant treatment costs of current treatments, the increasing challenges posed by drug and/ or antibiotic resistance, and the consequent need to discover new, more affordable, drugs. It is in this context that the use of dietary curcumin, an affordable, nontoxic, adjunct drug with no history of drug resistance, to treat infectious diseases needs to be seriously investigated.
Cytokines
Enzymes
Transcripon factors
Cancers Parasic
Hepac and biliary
Adhesion molecules
Inflammatory
Bacterial Micro RNAs
Cell cycle proteins
Curcumin Neuro degenerave
Viral
Cardio vascular
Renal Protein kinases
Metabolic
Apoptoc machinery
Growth factors
Receptors
Figure 1. Snapshot of Diseases that Could be Treated with Curcumin (Blue Circles) and its Molecular Targets (Black Circles).
number of diseases [3], with an equally large number of identified molecular targets (Figure 1) [4]. It has also been reported to be effective against pathogens causing infectious diseases [5]. Most of the clinical trials (more than 100, either completed or ongoing) focus on cancers and systemic disorders, and have trended toward a general positive outcome; however, these results need to be confirmed with well-planned, randomized designs. By contrast, there are few examples of clinical trials investigating curcumin as a treatment for infectious diseases, although many preclinical studies have indicated significant beneficial effects (see below).
curcumin would be to undertake clinical trials with select infectious diseases in which it would be possible to use curcumin as an adjunct drug to standard therapy and for which the treatment duration is short. With the development of resistance to antibiotics in general, curcumin may hold promise to ameliorate drug resistance, since it tends to decrease the toxicity and dose of the primary drug [3]. While most anti-infectives kill the pathogen by inhibiting fundamental molecular processes relating to its growth and survival, curcumin may offer protection through immunomodulation of the host response rather than by a direct killing effect on the pathogen. Thus, specific Curcumin as an Antimicrobial infectious diseases of major concern Agent where the potential for the use of curcumin Curcumin, which is extracted from tur- What is the Best Way Forward? meric, is a well-known enigmatic molecule We suggest that the best approach to has been demonstrated can be used to with potential health benefits in a large investigating the drug potential of study its efficacy in human clinical trials.
Trends in Pharmacological Sciences, Month Year, Vol. xx, No. yy
1
TIPS 1282 No. of Pages 3
Potential Diseases for Curcumin Adjunct Therapy Helicobacter[2_TD$IF] pylori[3_TD$IF] is a common human pathogen that infects half of the population of the world, and, in some cases, is responsible for inflammation of the gastric mucosa that leads to gastric cancer. Its incidence is higher in the developing world than elsewhere due to socioeconomic factors. Development of antibiotic resistance is also an issue. In a recent study in the mouse model of H. pylori infection, curcumin was shown to counteract all the inflammatory parameters based on cytokine, chemokine, and Toll-like receptor (TLR) PCR assays, and the C13 urea-breath test [6]. An encouraging development was the organization of a human clinical trial with 150 patients to study the impact of the addition of curcumin to a 10-day standard triple therapy (proton-pump inhibitor, clarithromycin, and amoxicillin) [7]. This is on the basis that curcumin may show synergistic effects, when used in combination therapy. Methicillin-resistant Staphylococcus aureus (MRSA) has been associated with considerable morbidity and mortality and is a major public health issue worldwide. The rapid spread of antibiotic resistance is posing a serious challenge to its treatment. MRSA has established itself as a common nosocomial pathogen and is being increasingly implicated in both healthcare- and community-associated infections [8]. Curcumin has been shown to significantly decrease the minimal inhibitory concentration of the antibiotics oxacillin, ampicillin, ciprofloxacin, and norfloxacin, which are currently used against MRSA. Curcumin–oxacillin treatment was shown to reduce bacterial counts below detectable limits within 24 h [9]. However, further studies are needed to determine the efficacy of this combination therapy in vivo. The combination of curcumin with the antimalarial drug arteether is effective in killing the murine malaria parasite, Plasmodium berghei. It is also effective in
2
preventing parasite recrudescence by inhibiting the inflammatory T helper type 1 (Th1) response and promoting the antiinflammatory Th2 response [10]. It is able to prevent sequestration of parasiteinfected red blood cells in the brain and the onset of neurological symptoms in experimental cerebral malaria (ECM). In particular, curcumin shows synergism with arteether in curing ECM after the onset of symptoms [11]. Mortality in cerebral malaria is as high as 15–25%, despite the use of primary treatment with artemisinin derivatives. Chagas disease, which is caused by infection with Trypanosoma cruzi, infects six– seven million people worldwide, mostly in Latin America, although the disease is now spreading to other continents. It can lead to cardiac and gastrointestinal complications, resulting in mortality and physical disabilities. The disease is curable with benznidazole and nifurtimox, when treated soon after infection, with efficacy decreasing the longer the infection lasts. Curcumin treatment has been shown to cause a significant reduction in macrophage infiltration and inflammation in both the heart and liver. Curcumin-treated infected mice displayed a 100% survival rate in contrast to the 60% survival rate commonly observed in untreated infected mice [12]. Therefore, it would be useful to test the efficacy of combination therapy with curcumin.
Concluding Remarks
Thus, curcumin as an adjunct drug would provide long-term benefits through immunomodulation, and this is especially relevant in cases where a vaccine is not available. As a start, specific examples where proof of principle exists for the efficacy of curcumin in vivo can be taken up for evaluation in the presence and absence of the primary drug in use. It is proposed that philanthropic organizations, such as the Bill & Melinda Gates Foundation, could promote preclinical and efficacy trials for assessing the benefits of curcumin and formulations that can enhance bioavailability, if considered necessary, as an adjunct drug in the examples discussed, where a substantial population in the developing countries is at risk. Since the treatments are for a relatively shorter period for infectious disease (relative to cancer, for example) and the end points are clearly quantifiable, this would help to establish curcumin as a viable, affordable adjunct drug to treat specific infectious diseases. An advantage to the study of infectious diseases is that the beneficial effects can be assessed in clear terms, unlike cancers, where more often the patient benefits can remain blurred by the long duration of treatment required and the complex nature of the disease. Such an approach would establish the use of curcumin backed by hard-core scientific and clinical evidence that may pave the way for its wider use. It might be that the use of curcumin as an adjunct drug rather than as a primary anticancer drug would elicit a credible beneficial response.
It would appear that curcumin may have beneficial effects in treating infectious diseases, despite issues with poor bioavail- Acknowledgments ability and rapid metabolism. It might be The research on the use of curcumin to treat experithat curcumin modulates immune mem- mental malaria in the authors’ laboratory was carried ory in the presence of either the pathogen out in a Centre of Excellence project supported by the Department of Biotechnology, Government of India. or antigen(s) from the pathogen generated G.P. is a senior scientist of the Indian National Science by the direct killing effect of the primary Academy. drug. In certain instances, it is able to aid the immune response and prevent fresh 1Department of Biochemistry, Indian Institute of Science, infection as well as to offer protection and Bangalore 560012, India cure long after the primary drug has dis- *Correspondence: [email protected] appeared from the system, as shown in (G. Padmanaban). the case of experimental malaria [10,11]. http://dx.doi.org/10.1016/j.tips.2015.09.007
Trends in Pharmacological Sciences, Month Year, Vol. xx, No. yy
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References 1. WHO (2012) Global Report for Research on Infectious Disease of Poverty, WHO 2. Bhutta, Z.A. et al. (2014) Global burden, distribution and interventions for infectious diseases of poverty. Infect. Dis. Poverty 3, 21 3. Gupta, S. et al. (2013) Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 15, 195–218 4. Shishodia, S. (2013) Molecular mechanisms of curcumin action: gene expression. Biofactors 39, 37–55 5. Moghadamtousi, S.Z. et al. (2014) A review on antibacterial, antiviral and antifungal activity of curcumin. BioMed Res. Int. 2014, 186864
6. Santos, A.M. et al. (2015) Curcumin inhibits gastric inflammation induced by Helicobacter pylori infection in a mouse model. Nutrients 7, 306–320 7. Rachel, G.B. Rabin Medical Center. The impact of addition of curcumin in 10 days triple therapy, on the eradication rate of Helicobacter pylori infection (CurHP). NCT02018328 8. Ray, P. et al. (2011) Methicillin-resistant Staphylococcus aureus in developed and developing countries: implications and solutions. Regional Health Forum 15, 74–82 9. Mun, S.H. et al. (2013) Synergistic antibacterial effect of curcumin against methicillin-resistant Staphylococcus aureus. Phytomedicine 20, 714–718
10. Vathsala, P.G. et al. (2012) Curcumin-arteether combination therapy of Plasmodium berghei-infected mice prevents recrudescence through immunomodulation. PLoS ONE 7, e29442 11. Dende, C. et al. (2015) Simultaneously targeting inflammatory response and parasite sequestration in brain to treat experimental cerebral malaria. Sci. Rep. 5, e12671 12. Nagajyothi, F. et al. (2012) Curcumin treatment provides protection against Trypanosoma cruzi infection. Parasitol. Res. 110, 2491–2499
Trends in Pharmacological Sciences, Month Year, Vol. xx, No. yy
3