In vitro and In silico studies on inhibitory effects of curcumin on multi drug resistance associated protein (MRP1) in retinoblastoma cells

Sreenivasan, Seethalakshmi; Ravichandran, S.; Vetrivel, Umashankar; Krishnakumar, Subramanian

doi:10.6026/97320630008013

Cited by 21 publications

(15 citation statements)

References 27 publications

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“…[23] However, extensive studies on the bioavailability of curcumin have to be done to know its distribution in tissues after administration at pharmacological dose. Thus, curcumin may be used as a chemosensitizer in cancer therapy to reverse the MDR in cancer cells.…”

Section: Resultsmentioning

confidence: 99%

“…[21] Various modulators have been identified to reverse MDR mechanisms and thus sensitize MDR cancer cells to anti-cancer agents. [22] Our recent study found that curcumin is an inhibitors of MRP1[23] and LRP,[24] which have been found to play an important role in the development of drug resistance in tumor cells. It has been reported that curcumin is able to modulate the expression and function of P-gp in human gastric carcinoma cells and primary cultures of rat hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

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Modulation of multidrug resistance 1 expression and function in retinoblastoma cells by curcumin

Sreenivasan

Ravichandran

Vetrivel

et al. 2013

Journal of Pharmacology and Pharmacotherapeutics

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Objective:To determine the possible interaction of curcumin with P-glycoprotein (P-gp) expression and function by in vitro and in silico studies.Materials and Methods:In this study, curcumin was compared for its potential to modulate the expression and function of P-gp in Y79 RB cells by western blot, RT-PCR (reverse transcription polymerase chain reaction) and functional assay. Further, in silico molecular modeling and docking simulations were performed to deduce the inhibitory binding mode of curcumin.Results:Western blot and RT-PCR analysis decreased the expression of P-gp in a dose-dependent manner. The effect of curcumin on P-gp function was demonstrated by Rhodamine 123 (Rh123) accumulation and efflux study. Curcumin increased the accumulation of Rh123 and decreased its efflux in retinoblastoma (RB) cells. In addition, curcumin inhibited verapamil stimulated ATPase activity and photoaffinity labeling study showed no effect on the binding of 8-azido-ATP-biotin, indicating its interaction at the substrate binding site. Moreover, molecular docking studies concurrently infer the binding of curcumin into the substrate binding site of P-gp with a binding energy of -7.66 kcal/mol.Conclusion:These findings indicate that curcumin suppresses the MDR1 expression and function, and therefore may be useful as modulators of multidrug resistance in RB tumor.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Modulation of multidrug resistance 1 expression and function in retinoblastoma cells by curcumin

Sreenivasan

Ravichandran

Vetrivel

et al. 2013

Journal of Pharmacology and Pharmacotherapeutics

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“…The MTT-bioassay data unambiguously showed that the pH-sensitive liposomal formulation of curcumin proved to significantly outclass the free drug in terms of The established high efficacy of formulated curcumin in resistant cells is of special interest, since this compound has been shown to restore the responsiveness to anticancer drugs and is considered as a potential multidrug-resistance reversal agent (Li et al, 2013;Li et al, 2011;Misra and Sahoo, 2011;Rao et al, 2014;Roy and Mukherjee, 2014;Sreekanth et al, 2011;Sreenivasan et al, 2012). The apoptosis assay firmly demonstrated that liposomal curcumin is a potent inducer of apoptotic DNA-fragmentation in HL-60, in compliance to preceding reports (Alaikov et al, 2007;Liao et al, 2008;Tan et al, 2006) and especially in HL-60/CDDP cells which proved to be more sensitive to the apoptogenic effects of equieffective levels of curcumin.…”

Section: Discussionmentioning

confidence: 99%

Curcumin loaded pH-sensitive hybrid lipid/block copolymer nanosized drug delivery systems

Jelezova

Drakalska

Momekova

et al. 2015

European Journal of Pharmaceutical Sciences

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Curcumin is a perspective drug candidate with pleiotropic antineoplastic activity, whose exceptionally low aqueous solubility and poor pharmacokinetic properties have hampered its development beyond the preclinical level. A possible approach to overcome these limitations is the encapsulation of curcumin into nano-carriers, incl. liposomes. The present contribution is focused on feasibility of using hybrid pH-sensitive liposomes, whereby curcumin is entrapped as a free drug and as a water soluble inclusion complex with PEGylated tertbutylcalix[4]arene, which allows the drug to occupy both the phospholipid membranes and the aqueous core of liposomes. The inclusion complexes were encapsulated in dipalmithoylphosphathydilcholine:cholesterol liposomes, whose membranes were grafted with a poly(isoprene-b-acrylic acid) diblock copolymer to confer pH-sensitivity. The liposomes were characterized by DLS, ζ-potential measurements, cryo-TEM, curcumin encapsulation efficacy, loading capacity, and in vitro release as a function of pH. Free and formulated curcumin were further investigated for cytotoxicity, apoptosis-induction and caspase-8, and 9 activation in chemosensitive HL-60 and its resistant sublines HL-60/Dox and HL-60/CDDP. Formulated curcumin was superior cytotoxic and apoptogenic agent vs. the free drug. The mechanistic assay demonstrated that the potent proapoptotic effects of pH-sensitive liposomal curcumin presumably mediated via recruitment of both extrinsic and intrinsic apoptotic pathways in both HL-60 and HL-60/CDDP cells.

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“…Finally, the simulated FC 60 +MRP-2 (=ABCC2) complex was characterized by the following parameters: the energy of interaction between the FС 60 and protein is -61.5 kJ/mol, the energy of steric clashes between the FС 60 and protein is 13.6 kJ/mol and, that importantly, in this case the binding pocket is completely filled ( Figure 2C The results of the molecular docking experiments suggest a direct interaction between FC 60 and three of the main proteins involved in multidrug resistance phenotypes of cancer cells -namely P-gp, MRP-1 and MRP-2. However, in a report devoted to analysis of interactions of MRP-1 with curcumin in silico, other aminoacid residues involved in formation of the protein binding cavity, were proposed [44]. The reason behind these differences may be the diverse modeling method used in this work and by Sreenivasan et al [44].…”

Section: Molecular Dockingmentioning

confidence: 93%

C60 fullerene enhances cisplatin anticancer activity and overcomes tumor cell drug resistance

et al. 2016

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A novel nano-formulation of the anticancer drug cisplatin (Cis) with C 60 fullerene (C 60 +Cis complex) was developed, demonstrating enhanced cytotoxic activity towards tumor cell lines in vitro n comparison to Cis alone. The enhanced proapoptotic activity of the novel complexes was found to be tightly connected with their unique capability to circumvent cancer drug resistance in vitro, as revealed by investigation of human leukemia cells HL-60 together with their sublines resistant towards doxorubicin (HL-60/adr, multidrug resistance protein-1=MRP-1=ABCC1 overexpressing) and vincristine (HL-60/vinc, P-glycoprotein=P-gp=ABCB1 overexpressing). The enhanced anticancer activity of the developed С 60 +Cis complexes was also confirmed in vivo on male C57BL/6J mice bearing Lewis lung carcinoma, effectively inhibiting tumor growth and formation of metastases in comparison to free single Cis. For better understanding of molecular mechanisms underlying the potential ability of the С 60 +Cis complexes to circumvent cancer drug resistance, a molecular docking study was conducted. This analysis demonstrated the potential capability of C 60 fullerene to form van der Waals interactions with potential binding sites of P-gp, MRP-1and MRP-2 (ABCC2) molecules, with maximum affinity to MRP-2. The observed phenomenon might indicate the mechanism how the C 60 +Cis complex bypasses drug resistance of cancer cells by direct binding to ABC transporter proteins. Additionally, the results of Ames mutagenicity test demonstrated that immobilization of Cis on С 60 fullerene significantly diminishes mutagenic activity of Cis and may reduce the probability of secondary neoplasms induction. Concluding, the synthesized C 60 +Cis complex effectively induces cancer cell death in vitro and inhibits tumor growth in vivo, circumventing cancer cell resistance to chemotherapy due to the specific affinity of C 60 fullerene towards ABC-transporter proteins. The obtained results indicate the C 60 +Cis complex as a promising novel chemotherapeutic agentespecially for treatment of drug-resistant tumors.

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In vitro and In silico studies on inhibitory effects of curcumin on multi drug resistance associated protein (MRP1) in retinoblastoma cells

Cited by 21 publications

References 27 publications

Modulation of multidrug resistance 1 expression and function in retinoblastoma cells by curcumin

Modulation of multidrug resistance 1 expression and function in retinoblastoma cells by curcumin

Curcumin loaded pH-sensitive hybrid lipid/block copolymer nanosized drug delivery systems

C60 fullerene enhances cisplatin anticancer activity and overcomes tumor cell drug resistance

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