Synergistic effects of curcumin and its analogs with other bioactive compounds: A comprehensive review

doi:10.1016/j.ejmech.2020.113072

European Journal of Medicinal Chemistry

Volume 210, 15 January 2021, 113072

https://doi.org/10.1016/j.ejmech.2020.113072 Get rights and content

Highlights

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Synergetic anticancer, antimalarial, and anti-inflammatory effects of curcumin with other bioactive compounds are discussed.
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Possible mechanism for synergetic effect of curcumin and its analogs with other drugs or bioactive compounds are covered.
•
Curcumin hybrids and their activity are presented.

Abstract

Curcumin, as a natural compound, extracted from plant Curcuma longa, is abundant in the Indian subcontinent and Southeast Asia, and have been used in a diverse array of pharmacological activities. Although curcumin has some limitations like low stability and low bioavailability, it has been proved that this compound induced apoptosis signaling and is also known to block cell proliferation signaling pathway. Recently, extensive research has been carried out to study the application of curcumin as a health improving agent, and devise new methods to overcome to the curcumin limitations and incorporate this functional ingredient into foods. Combinational chemotherapy is one of the basic strategies is using for 60 years for the treatment of various health problems like cancer, malaria, inflammation, diabetes and etc. Molecular hybridization is another strategy to make multi-pharmacophore or conjugated drugs with more synergistic effect than the parent compounds. The aim of this review is to provide an overview of the pharmacological activity of curcumin and its analogs in combination with other bioactive compounds and cover more recent reports of anti-cancer, anti-malarial, and anti-inflammatory activities of these analogs.

Graphical abstract

Introduction

Herbal medicine has been used from ancient times to the present day and has had lots of progress for healing purposes. Curcumin which is extracted from the rhizome of Curcuma longa L. is one of the most ancient medicinal herbs and is being used for the treatment of various health problems for a thousand hundreds of years in Indian system of medicine [1,2]. Curcumin possesses a wide range of therapeutic effects such as anti-inflammatory [[3], [4], [5], [6], [7]], antioxidant, anticancer [[8], [9], [10], [11]] and antimicrobial [[12], [13], [14]]. Curcumin/curcumin analogs contain O-methoxy phenolic groups resulting in possessing high antioxidant activity [7,8,15]. Curcumin alters the expression of cytokines [16], transcription factors [17], and enzymes which are involved in cell vitality [18]. Although there are several evidences related to the safety and efficacy of curcumin, it has some limitation related to its bioavailability, stability at physiological pH, and its metabolism inside the cell. Combination therapy and molecular hybridization are effective approaches to improve the curcumin limitation.

Combinational drug therapy is an interesting approach for the treatment of various diseases. In the 1960s, scientists used a combination of antibiotics to reduce the risk of resistance for tuberculosis treatment [19]. This achievement has inspired them to use this method for cancer treatment, and they found this method effective for lung, breast and colon cancer treatment [20]. Moreover, studies on this method for the treatment of other health conditions like Parkinson’s disease [21], inflammation [22] and malaria [23] have been continued. Results revealed that in many cases, combinational therapy increased the healing chance and response rate, and decreased drug resistance in patients with long-term chronic conditions such as cancer, diabetes, and cardiovascular disease [[24], [25], [26]]. Recent studies reported that a treatment modality that combines curcumin or curcumin analogs with other therapeutic agents enhanced efficacy compared to the mono-therapy [27].

Molecular hybridization is a powerful medicinal chemistry strategy to make multifunctional or conjugated drugs by combining two pharmacophoric groups or two (or more) biological active compounds. Hybrid compounds, which can obtain via the covalent chemical bond between the two active fragments/pharmacophores, may have more synergistic effect than the parent compounds and improved pharmacokinetic and pharmacodynamic profiles. Moreover, this strategy helps in reducing the side effects and economic in some costly drug therapy. Although hybrid compounds may minimize the risk of drug-drug interaction and decrease drug resistance, selecting the right target combination is the critical issue [[28], [29], [30]]. Curcumin hybrids recently are tested for the treatment of cancers, Alzheimer’s disease (AD) and Parkinson disease (PD).

Section snippets

Synergistic effect of curcumin and its analogs on anticancer activity

Cancers have become a major health problem and the second cause of death in the world. In the past, chemotherapy with a single drug was used for cancer treatments, but nowadays, mostly, combination chemotherapy is recommended [31]. Using combination cancer chemotherapy has several advantages such as decreasing the chance of tumor resistance [32], providing efficient and effective results at an affordable cost [30], and decreasing the drug dosage [33,34]. Combination cancer chemotherapy is used

The synergistic effect of curcumin on antimalarial activity

Malaria caused by Plasmodium genus leads to high morbidity and mortality, especially in the Africa region [96]. Artemisinin (41) (Fig. 3), a drug which is derived from the Asian plant Artemisia annua, is one of the most rapidly acting antimalarial drug. This drug has shown some side effects like skin rash, nausea, vomiting, and tremors [97] (Table 2). Besides, Plasmodium genus resistance to this drug has recently encouraged the researchers to employ the combination therapy as antimalarial

Synergistic effect of curcumin on anti-inflammatory activity

Upon invasion microorganisms like human pathogens, dust particles, and viruses, the body utilizes inflammation in two different patterns [102] one is the acute inflammation, which is a short-term response that results in healing by inducing the infiltration of leukocytes into the damaged region, elimination of stimulus, and tissue repair. The other is chronic inflammation that is the long-term, involved in tissue destruction and attempts to tissue repair. This type of inflammation plays a great

Synergistic effect of curcumin on antioxidant activity

Antioxidants play an important role in interacting with free radicals and terminating the chain reaction before damaging the vital molecules. There are some natural enzyme systems in the body which can disarm free radicals like vitamin E and vitamin C. After neutralizing the free radicals by these natural antioxidants, these compounds will convert to the free radicals, and so they can damage some cells. Since the body cannot make these anti-oxidants, so they must be supplied in the diet.

Synergistic effect of curcumin on other diseases

Curcumin combination therapy is even used for the treatment of various diseases, like cystic fibrosis, PD and diabetes. In general, this approach is used for the treatment of cystic fibrosis (CF) potentiator VX-770 (ivacaftor/KALYDECO™), as a drug which can target defective gating of cystic fibrosis transmembrane conductance regulator (CFTR) mostly with G551D, S1251 N mutation. Since this drug does not normalize CFTR-dependent biomarkers, Dekkers et al. [124] studied in vivo synergistic effects

Synergistic effect of curcumin hybrids

Noureddin et al. [131], recently published an excellent review on the structures, biological activities of both curcumin analogs and their hybrid molecules. Structure activity relationship (SAR) of curcumin analogs and hybrids demonstrated the improved anti-cancer, anti-inflammatory and antioxidant activities. This paper also nicely discussed on improved bioavailability of synthesized analogs compared to curcumin. The possible structural features responsible for curcumin’s activity are the

Conclusion

Curcumin has a wide range of therapeutic effects and is used for the treatment of several disorders like cancer, malaria, Parkinson’s, and Alzheimer’s disease. Despite all the advantages, it has some limitations like low bioavailability and weak stability. The combinational therapy and molecular hybridization which are being used for the improvement of these limitations. Regarding the combinational therapy, studies revealed that some curcumin combined compounds showed more anti-inflammatory,

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Review articleSynergistic effects of curcumin and its analogs with other bioactive compounds: A comprehensive review

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Synergistic effect of curcumin and its analogs on anticancer activity

The synergistic effect of curcumin on antimalarial activity

Synergistic effect of curcumin on anti-inflammatory activity

Synergistic effect of curcumin on antioxidant activity

Synergistic effect of curcumin on other diseases

Synergistic effect of curcumin hybrids

Conclusion

Declaration of competing interest

Food Chem.

Life Sci.

Life Sci.

J. Surg. Res.

J. Biol. Chem.

Clin. Nutr.

Lancet Lond. Engl.

Cell Rep.

Lancet Lond.

Crit. Rev. Oncol. Hematol.

Fitoterapia

Mater. Sci. Eng. C

Arch. Biochem. Biophys.

J. Exp. Clin. Cancer Res. CR.

Eur. J. Pharm. Biopharm.

Bioorg. Med. Chem.

Biochem. Biophys. Res. Commun.

Neurochem. Int.

Eur. J. Pharmacol.

Biomaterials

Canc. Lett.

Evid. Based Compl. Alternative Med.

Adv. Exp. Med. Biol.

The chemistry of curcumin: from extraction to therapeutic agent

Molecules

J. Ethnopharmacol.

Ann. Nutr. Metab.

Exp. Hematol.

Synthesis. evaluation of cytotoxic properties of promising curcumin analogues and investigation of possible molecular mechanisms

Chem. Biol. Drug Des.

Recent advances of curcumin and its analogues in breast cancer prevention and treatment

RSC Adv.

Agents Chemother.

J. Nanobiotechnol.

Chem. Biodivers.

Food Sci. Biotechnol.

mBio

Mol. Canc. Therapeut.

J. Diabetes Res.

PLoS Med.

Med. J. Aust.

Nat. Rev. Canc.

Oncotarget

Molecules

Curr. Top. Med. Chem.

Eur. J. Med. Chem.

Canc. Treat Rep.

Mol. Interv.

J. Am. Chem. Soc.

BMC Canc.

AAPS J.

BMC Canc.

Review article
Synergistic effects of curcumin and its analogs with other bioactive compounds: A comprehensive review