Journal of Tropical Medicine

Review Article

The Potential use of a Curcumin-Piperine Combination as an Antimalarial Agent: A Systematic Review

Table 1

Several studies related to curcumin as an antiplasmodium.


No	Activities	Subject	Type of study	Findings/outcomes	References

1	Antioxidant	Chloroquine-resistant P. falciparum and P. berghei-infected mice	In vitro	Curcumin (IC₅₀:5 μM) inhibits chloroquine-resistant P. falciparum growth in culture	[27]
1			In vivo	Curcumin (100 mg/kg BW) reduces blood parasitemia by 80–90% and significantly enhances their survival	[27]
2		P. berghei-infected mice	In vitro	Curcumin and artemisinin combination show an additive interaction in killing P. falciparum	[41]
2		P. berghei-infected mice	In vivo	Three oral dependent doses of curcumin following a single injection of alpha, beta-arteether can inhibit recrudescence due to alpha, beta-arteether monotherapy and also ensure almost 100% survival rate of the animal models.	[41]
3		CQS (3D7 and D10) and CQR strains (Dd2 and 7G8) of P. falciparum	In vitro	Curcumin (25–100 μM) caused specific inhibition of PfGCN5 HAT	[42]
4		P. berghei ANKA-infected mice	In vivo	The combination of these two herbal drugs (AP + CUR, HC + CUR) inhibited the ring stage of the parasite with no in vivo toxicity	[43]
5		P. falciparum 3D7 line was cultured in human 0⁺ erythrocytes	In vitro	Curcumin inhibited P. falciparum glyoxalase (GloI)	[44]
6		-	Docking and in silico ADMET	Curcumin inhibits PfSAHH (Plasmodium falciparum S-adenosyl-L-homocysteine hydrolase)	[45]
7		P. berghei-infected mice and murine RAW 264.7 macrophages	In vivo	Encapsulation of curcumin in PLGA increased parasite suppression by 56.8% at 5 mg/kg of nanoformulation, which was higher than free curcumin (40.5%) at 10 mg/kg	[46]
7		P. berghei-infected mice and murine RAW 264.7 macrophages	In vitro	The IC₅₀ of Cur-PLGA (292.6 μg/mL) was lower than free curcumin (1000 μg/mL)	[46]
8		P. falciparum	In silico simulation study	Curcumin shows a high affinity for binding with HGPRT of PfHGPRT as virulence factors in malaria progression	[47]
9		P. vivax was cultured in RPMI 1640 culture medium (with 10% human serum and gentamycin 2 μg/ml) at 37°C in a 5% CO₂ incubator	In vitro	Ethanol extracts of Curcuma caesia and Curcuma longa showed significant parasitemia inhibition ranging from 5.875.6% and 2–29.8% against Chloroquine-resistant P. vivax	[48]
10		Chloroquine-resistant P. falciparum INDO strain and P. berghei (ANKA) infected BALB/c mice	In vitro	Curcumin-loaded in FΔF nanotubes showed P. falciparum inhibition (IC₅₀, 3.0 μM) compared to free curcumin (IC₅₀, 13 μM)	[49]
10			In vivo	Ccm-FΔF (equivalent to 50 mg/kg BW of curcumin) significantly decreased parasitemia and increased life span compared to free curcumin	[49]
11		Chloroquine (CQ) sensitive strain of P. yoelii (N-67)	In vitro	Curcumin-bound chitosan nanoparticles can traverse the mucosal barrier intact and inhibited parasite lysate in a dose-dependent manner, with a lower IC₅₀ value than chloroquine.	[29]
11		Chloroquine (CQ) sensitive strain of P. yoelii (N-67)	In vivo	Curcumin bound to chitosan nanoparticles (1 mg) shows 100% survival	[29]
12		3D7 (chloroquine-sensitive strain) and P. berghei (ANKA) infected C57BL/6 mice	In vitro	Nanotized curcumin (IC₅₀: 0.5 μM) inhibited ten-fold more P. falciparum than its native counterpart (IC₅₀: 5 μM)	[50]
12			In vivo	Nanotized curcumin (20 mg/kg BW and 4 0 mg/kg BW) prolonged the survival of mice by more than 2 months with complete clearance of parasites compared to the untreated animals	[50]
13		Chloroquine-sensitive 3D7 (West Africa) and chloroquine-resistant RKL-2 strain (Raurkela, Orissa, India) of P. falciparum	In silico	Curcumin analog showed various functional groups of curcumin and its analogs against the PfATP6 protein	[51]
13			In vitro		[51]
14		Sensitive 3D7 strain of P. falciparum	In vitro	50 μg/mL of six curcumin derivates showed 100% schizont inhibition	[52]
15		3D7 chloroquine-sensitive strain of P. falciparum	In vitro	Curcumin (5 μM) produced ROS which induced cytotoxicity and disrupted plasmodium microtubule stabilization, schizogony, and apicoplast segregation	[31]
16		P. falciparum drug-susceptible 3D7 clone of the NF54 isolate and the K1 strain (chloroquine and pyrimethamine resistant)	In vitro	Curcumin (10 μM) induced intracellular ROS production resulting in PPARɣ/Nrf2 activation, increasing CD36 expression in monocytes/macrophages for phagocytosis of infected red blood cells	[30]
17		—	In vitro	Curcumin (0.4 mM) inhibits formation of β-hematin with an efficiency of 78.8% compared to amodiaquine (91.8%) and DMSO (10.7%)	[13]
18		A chloroquine-resistant strain of P. falciparum (MRC-pf-303) cultured in human O⁺ washed erythrocytes and P. berghei ANKA-infected mice	In vitro	Curcumin (IC₅₀:17.4 μM) inhibited parasites at their ring stage	[53]
18			In vivo	Andrographolide-curcumin reduced parasitemia (29%) compared to the control (81%), as well as prolonged life span 2-3 fold	[53]
19		Chloroquine (CQ) sensitive (D6 clone) and CQ-resistant (W2 clone) strains of P. falciparum	In vitro	Curcuminoids (IC₅₀: 2 μM) inhibited PfTrxR	[54]
20		Chloroquine-sensitive (CQ-S) and chloroquine-resistant (CQ-R) P. falciparum	In vitro	Several curcumin analogs effectively inhibited P. falciparum growth compared to curcumin. The most potent curcumin compounds 3, 6, and 11 were inhibitory for CQ-S P. falciparum at IC₅₀ of 0.48, 0.87, 0.92 μM and CQ-R P. falciparum at IC₅₀ of 0.45 μM, 0.89 μM, 0.75 μM, respectively	[55]
21		P. falciparum recombinant PfGST isolated from E. coli cells	In vitro	Curcumin inhibits PfGST with IC₅₀: 69 μM	[56]
22		P. yoelii-infected mice	In vivo	Curcumin-loaded eudragit-nutriosomes increased the survival of malaria-infected mice relative to free curcumin-treated control	[57]
23		P. falciparum chloroquine-resistant (W2) and chloroquine-sensitive (3D7) strains were maintained in continuous culture using human RBCs	In vitro	Coencapsulated NCs exhibited a significant reduction in P. falciparum parasitemia, better than QN/CR, and prolonged survival rate	[58]
23			In vivo		[58]
24		P. berghei NK-65 infected mice	In vivo	Both nano encapsulated artemisinin (50 mg/kg/day) and artemisinin plus curcumin (100 mg/kg/day) cured all malaria-infected mice within the same postinoculation period	[59]
25		—	Molecular docking	The binding of curcumin and its analogs to Ca (2+) ATPase (PfATP6) of P. falciparum (the target of many antimalarial drugs) is mediated by both hydrophobic and polar interactions	[60]
26		P. berghei-infected mice	In vivo	Nanotized conjugate curcumin formulation can prolonge life span 90 days with complete eradication of the parasites from RBC	[61]
27		P. falciparum (intraerythrocytic forms, strain NF54).	In vitro	Curcuma exhibited high activity (IC_50:<2.5 μg/mL) against parasites of the genera leishmania, trypanosoma, and Plasmodium	[7]
28		P. berghei-infected mice	In vivo	Curcuminoid-loaded liposomes (40 mg/kg BW) along with α/β arteether (30 mg/kg BW) cured infected mice and prevented recrudescence	[62]
29		P. berghei-infected mice	In vivo	Curcumin-nanostructured lipid carriers (Cur-NLC) was significantly higher compared with that of free cur at the dose of 40 mg/kg/day	[63]
30		P. berghei	In vivo	CA-PLGA nanoparticle 5 and 10 mg/kg doses. The drug efficacy was determined on day 5 and 8.	[64]
31		P. berghei-infected mice	In vivo	A combination of 35 mg/kg of curcumin along with either 5 mg/kg or 1 mg/kg BW of PRI demonstrated 100% antimalarial activity and survivability beyond 20 days	[65]
32		P. berghei ANKA-infected mice	In vivo	Curcumin 50 mg/kg/day reduced parasitemia and increased the survival rate	[66]
33		P. berghei-infected mice	In vivo	Curcumin 100 mg/kg BW showed a 2-fold increase in the survival period (15–21 days) compared to those treated with the free curcuminoids at the same dose	[67]
34		ART-resistance clone of P. chabaudi	In vivo	Curcumin 300 mg/kg/day and piperine 20 mg/kg/day had only a modest antimalarial effect and could not reverse the artemisinin-resistant phenotype	[28]
34		ART-resistance clone of P. chabaudi	In vitro		[28]
35		P. chabaudi-infected mice	In vivo	Curcumin 500 mg/kgBW, piperine 20 mg/kgBW and choloroquine 2.5 mg reduced parasitemia to 37% seven days after treatment compared to the control group 65%	[68]

36	Anti-inflammatory	P. berghei ANKA-infected mice	In vivo	PLGA-curcumin (5 mg/dose providing 350 μg of curcumin) was 15-fold lower in preventing the breakdown of blood-brain barrier and inhibition of brain mRNAs for inflammatory cytokines, the chemokine receptor CXCR3 and its ligand CXCL10, with an increase in the inflammatory cytokine IL-10	[69]
36		P. berghei ANKA-infected mice	In vivo	PLGA-curcumin inhibiting the sequestration of parasitized-RBCs and CD8⁺T cells in the brain	[69]
37		P. berghei-infected mice	In vivo	Curcumin α, β arteether combination (5 mg + 750 μg) prevents recrudescence through immunomodulation in P.berghei-infected mice	[70]
38		P. berghei-infected mice	In vivo	Curcumin 5 mg reversed all parameters: Inflammatory responses, CD8⁺ T cell, and pRBC sequestration into the brain and blood-brain barrier (BBB) breakdown	[71]
39		P. berghei ANKA-infected mice	In vivo	Curcumin and lipid-based drug delivery systems (LBDDSs) combined with β-arteether (30 mg/g) reduced cytoadherence and subsequent parasite sequestration of parasite-infected erythrocytes by inhibiting NF-kB activation, thereby suppressing proinflammatory cytokine responses and expression of adhesion molecules in endothelial cells	[72]
40		P. berghei NK65-infected rat	In vivo	Curcumin 30 mg/kg BW involved inhibition of GSK3β	[73]

41	Antiapoptotic	P. falciparum chloroquine-resistant strain (TM 267)	In vitro	Curcumin IC₅₀ ∼10 μM decreased bEnd.3 apoptosis to 60.0% and 79.6% upon pretreatment and cotreatment, respectively, with Pf-IRBC, platelets, and PBMC	[74]