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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 12  |  Page : 1193-1200

Combinatorial effect of curcumin and tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) in induction of apoptosis via inhibition of nuclear factor kappa activity and enhancement of caspase-3 activity in chronic myeloid cells: An In-vitro study


1 Department of Physiology, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Biotechnology, Era's Lucknow Medical College & Hospital, Era University, Lucknow, Uttar Pradesh, India
3 Department of Obstetrics and Gynaecology, King George's Medical University, Lucknow, Uttar Pradesh, India
4 Department of Zoology, Lucknow University, Lucknow, Uttar Pradesh, India
5 Department of Biochemistry, King George's Medical University, Lucknow, Uttar Pradesh, India

Date of Web Publication11-Dec-2018

Correspondence Address:
Archna Ghildiyal
Department of Physiology, King George's Medical University, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_348_18

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 > Abstract 


Background: Nuclear factor kappa B (NFkB-light-chain-enhancer of activated B-cells) expression and its regulation is a key role in the development of number of malignancies, as NFkB mediates the balance between cell death and its survival. Therefore, NFkB regulation constitutes an attractive target to overcome the resistance to chemotherapeutic agents in anticancer therapy. Curcumin, as a chemopreventive agent, has a potential role in inhibiting cell growth in a variety of malignancies. Thus, this study was aimed to investigate the efficacy of curcumin along with tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) in KCL-22 myeloid cells along with an investigation of the mechanism by which both the agents exert their effects.
Materials and Methods: KCL-22 cells were exposed to different doses of curcumin and TRAIL alone and in combination. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, caspase activity by fluorescent method, protein expression by western Blot, and NFkB activity by electrophoretic mobility shift assays, respectively.
Results: Cell viability assay revealed that when both the agents, curcumin and TRAIL, were used together, there was reduced cell viability in dose- and time-dependent manner as compared to each agent alone. Curcumin and TRAIL enhanced the caspase-3 activity as compared to caspase-8 and caspase-9. Both the agents induced apoptosis in KCL-22 cells by suppressing the IκB kinase and NFkB activity.
Conclusion: Our results conclude that curcumin and TRAIL effectively induce the apoptosis through the inhibition of NFkB activity and by enhancing the caspase-3 activity. Thus, curcumin may prove as a potent inhibitor of NFkB by representing its role in cancer pathogenesis, especially in chronic myeloid leukemia cells.

Keywords: Caspases, chronic myeloid leukemia, curcumin, IκB kinase, nuclear factor kappa, tumor necrosis factor-α-related apoptosis-inducing ligand


How to cite this article:
Iqbal B, Ghildiyal A, Singh S, Siddiqui S, Kumari P, Arshad M, Mahdi A A. Combinatorial effect of curcumin and tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) in induction of apoptosis via inhibition of nuclear factor kappa activity and enhancement of caspase-3 activity in chronic myeloid cells: An In-vitro study. J Can Res Ther 2018;14, Suppl S5:1193-200

How to cite this URL:
Iqbal B, Ghildiyal A, Singh S, Siddiqui S, Kumari P, Arshad M, Mahdi A A. Combinatorial effect of curcumin and tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) in induction of apoptosis via inhibition of nuclear factor kappa activity and enhancement of caspase-3 activity in chronic myeloid cells: An In-vitro study. J Can Res Ther [serial online] 2018 [cited 2019 Sep 21];14:1193-200. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/1193/245021




 > Introduction Top


Chronic myeloid leukemia (CML) is a malignant clonal disorder of hematopoietic stem cells prompting monstrous extension of myeloid lineage cells.[1] The disease is specified by anemia, granulocytosis, basophilia, thrombocytosis, and splenomegaly. The fate of CML is to advance from a benign chronic phase into the fatal blast crisis between 3 and 5 years. CML accounts for about 20% of all cases of leukemia and the estimated death rate is about 1.5/100,000 populations per year. The disease is more dominant in men than in women. CML tends to be a disease of middle life with a slowly increasing age trend in Western countries. The incidence of CML is in the age range of 40–60 years.

Curcumin (diferuloylmethane), the main active polyphenol derived from the rhizomes of Turmeric (Curcuma longa), inhibits cell proliferation, inflammation, and induces cell cycle arrest and apoptosis in variety of cancers.[2],[3] Curcumin is most commonly used in our kitchen as a flavoring agent and has also prompted studies aimed to unfold its mechanism as an anticancer agent. It also enhances apoptosis.[4] Apoptosis is triggered by two major pathways: the death pathway and the mitochondrial pathway.[5] Both the pathways result in the activation of various caspases, which in turn execute the apoptotic pathways.[6]

Various studies have demonstrated that curcumin exerts antiapoptotic activity by enhancing the production of caspases in a variety of cancers.[7] Importantly, curcumin exerts its cytotoxic effect in a number of ways, including cell cycle arrest, caspase activation, and transcriptional factors activation. Curcumin can execute different mechanisms of cancer cell death depending on the type of tumor cell. For example, curcumin causes cell death through apoptosis in prostate cancer and lung cancer,[8] whereas in pancreatic cancer through mitotic catastrophe.[9] Curcumin reduces cell proliferation and increases the cell death in various hematological malignancies.[10]

Tumor necrosis factor (TNF)-α-related apoptosis-inducing ligand (TRAIL) is a cytokine of the TNF family which is capable of inducing apoptotic cell death in a variety of cancer cell types without harming normal cells.[11] TRAIL binds to its four death receptors includes DR4, DR5, DcR1, and DcR2. DR4 and DR5 are highly expressed on cancer cells and are necessary for TRAIL-induced apoptosis.[12] DcR1 and DcR2 receptors are expressed in healthy cells and are unable to initiate apoptotic responses.[13] Previous studies have demonstrated that few cancers are resistant to the apoptotic effects of TRAIL.[14] Combined therapy of cytotoxic agent and TRAIL may sensitize the TRAIL-resistant cancer cells which may prove an effective cancer therapy for TRAIL-mediated apoptosis.

Nuclear factor kappa B (NFkB) is a ubiquitous transcription factor which plays an important role in the development of cells. The unregulated control of NFkB has been associated with the generation of various diseases including viral replication, radiation damage, and cancer.[15],[16] This property makes NFkB an essential target for therapeutic efficacy. Various chemotherapeutic agents inhibit NFkB activation in a number of cancer cells by regulating its survival signals, thus making them resistant to treatment.[17],[18] Previous studies have shown that curcumin is an effector modulator for NFkB-dependent pathological cancers.[19]

In this study, we investigated whether curcumin alone or in combination with TRAIL can induce cell death in CML cells KCL-22. We studied the mechanism by which both the agents induce apoptotic effects.


 > Materials and Methods Top


Cell lines

CML cells KCL-22 were a generous gift from Dr. Santu Bandyopadhyay, IICB, Kolkata. KCL-22 cells were maintained in RPMI 1640 (Invitrogen) media supplemented with 10% FBS (Invitrogen), 0.2% sodium carbonate (Merck), and ×1 solution of antibiotics at 37°C in a humidified atmosphere of 5% CO2. Cell viability was checked by standard trypan blue dye exclusion.

Drugs and antibodies

Curcumin was purchased from Sigma-Aldrich (St. Louis, USA), dissolved in dimethyl sulfoxide (DMSO) as a stock concentration of 100 mmol/L and stored in the dark condition at −20°C. All the required concentrations were prepared by diluting the stock solution in the culture media. TRAIL was procured from R&D Minneapolis. Caspases-3, 8, and 9 activities were measured by the fluorescent kit method (R&D Systems, USA). All the experiments were performed in triplicates.

Cell viability measurement

Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye reduction assay.[20] KCL-22 cells (2 × 104) were briefly plated in each well of 96-well culture plate for overnight at 37°C and 5% CO2. Stock solutions of the compound were diluted to obtain the desired concentrations (10, 25, 50, 75, 100, and 150 μM) in the culture medium. Thereafter, 10 μL of MTT (5 mg/ml of media without phenol red and serum) solution was added in each well after 24 and 48 h of treatment, and then incubated for 3 h at 37°C. The formazan crystals formed were dissolved in 100 μL of DMSO after the removal of supernatant for 10 min at 37°C. The optical density was recorded at 540 nm by a microplate reader (BIORAD-680).

The percentage viability was calculated using the following formula:

% Cell viability = {(OD of treated) (OD of control)} × 100

The plot of % cell viability versus CQ concentrations was used to analyze the concentration lethal to 50% of the cells (IC50). The cellular morphological changes were observed under inverted phase-contrast microscopy (Nikon ECLIPSE Ti-S, Japan).

Fluorometric caspase-3 activity assay

Direct measurements of caspase activity were performed using colorimetric protease kits (R and D Systems, USA), according to the manufacturer's recommendations, after the incubation of cells with curcumin (50μM) and TRAIL (25 ng/mL) alone and in combination for 24 h. The caspase activity assay is based on the spectrophotometric detection of the para-nitroaniline (pNA) chromophore after cleavage from the substrates X-p NA, where X stands for amino acid sequences recognized by specific caspase-6 (VEIDI-pNA), caspase-8 (IETD-pNA), and caspase-9 (LEHD-pNA). 2 × 106 KCL-22 cells were briefly pelleted by centrifugation and lysed on ice. The protein concentration in the lysate was measured using a Bio-Rad Protein assay (Bio-Rad Laboratories Inc., USA). The cell lysates were then incubated with each X-p NA substrate (200 μM final concentration) at 37°C in a microtiter plate. The optical density of samples was measured at 405 nm. After subtraction of the blank, the increase in caspase activity was determined by comparing these results with the levels of the control.

Western blot analysis

Controls and curcumin and TRAIL treated and untreated cells were lysed with radioimmunoprecipitation assay (RIPA) buffer 10 mM Tris–HCl, pH 8.0, 0.5 mM EDTA, 150 mM NaCl, 1% NP40, 0.1% SDS, 5 mg/mL deoxycholic acid, 1 mM DTT, 2 mM PMSF, 2 mM Na3 VO4, 10 mM NaF, 1 μg/mL leupeptin, and 1 μg/mL aprotinin. KCL-22 cells (2 × 106 cells) were collected and washed twice with cold phosphate-buffered saline. Cellular pellets were then incubated with 400 μL of cold RIPA buffer for 15 min. Cellular pellets were then centrifuged at 8000 × g at 4°C for 10 min, and the supernatants were collected and immediately stored at −20°C. Protein concentration of the lysates was determined using the Bradford reagent (Sigma–Aldrich). About 25 μg cell lysates were resolved on 10% SDS-PAGE under reducing condition and then electrotransferred to nitrocellulose membrane of pore size 0.2 μM for 7 min. The membranes were blocked with 5% BSA in wash buffer for 1 h. Then, they were washed thrice with wash buffer (TBS, 0.1% Tween-20) and incubated with primary antibodies (Abs) diluted in blocking buffer with gentle shaking overnight. On the next day, the membranes were washed three times with wash buffer and then incubated with HRP-conjugated secondary antibody for 1 h. Detection of HRP-conjugated Abs was done by Super Signal West Pico Chemiluminescent Substrate (Perice, USA) and developed on X-ray film in a dark room.

Electrophoretic mobility shift assays

To evaluate the effect of curcumin and TRAIL on NFkB activation, we carried out electrophoretic mobility shift assay (EMSA) as described previously.[21] In brief, nuclear extracts were incubated with Cy3-labeled NFkB double-stranded oligonucleotides (5'-AGTTGAGGGGACTTTCCCAGGC-3' and 3'-GCCTGGGAAAGTCCCCTCAACT-5'), at room temperature in binding buffers (250 mM HEPES,10 mM KCL,1 mM EDTA,10 mM DTT, 1 mM PMSF, and 100 mM NaCl), 1μg poly (dI-dC), 1μg tRNA, and 10% glycerol for 20 min. The protein: dsDNA mixtures were fractionated on 5% PAGE in 0.5 × TBE buffer (89 mM TRIS, 89 mM boric acid, and 2 mM MgCl2) at 6°C. The gel was quantified by Typhoon phosphoimager (typhoon FLA TRIO, Bioscience).

Statistical analysis

Cell viability data were expressed as the mean ± standard error of the mean from triplet experiments. One-way ANOVA and Dunnett's multiple comparison test were done using GraphPad Prism (Version 5.01) software for significance test, using P ≤ 0.05.


 > Results Top


Effect of curcumin and tumor necrosis factor-α-related apoptosis-inducing ligand on cell viability of KCL-22 cells

Antiproliferative effect of curcumin and TRAIL on chronic myeloid cell line KCL-22 was studied by MTT assay in time- and dose-dependent manner. KCL-22 cells were treated with different concentration of curcumin, followed by TRAIL at 24 h and 48 h of treatment. Results indicated that curcumin alone decreases cell viability in dose-dependent manner approximately by 92%, 73%, 52%, 35%, and 22% at 10 μM, 25 μM, 50 μM, 75 μM, and 100 μM, respectively, at 24 hours of treatment, whereas it became 82%, 70% 48%, 28%, and 14% at 48 h of treatment [Figure 1]. On addition of TRAIL (100 nM) with curcumin, cell viability reduced approximately ten folds [Figure 2]. Overall, the results showed that the amount of cell viability reduced by combined treatment of curcumin and TRAIL which was more pronounced in comparison to their individual effect.
Figure 1: Effect of different doses of curcumin on cell viability on KCL22 cells at 24 h and 48 h of treatment. Significant differences compared with untreated control are indicated by: *P < 0.05; **P < 0.01

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Figure 2: Effect of tumor necrosis factor-α-related apoptosis-inducing ligand alone and in combination with curcumin on cell viability on KCL22 cells at 24 h and 48 h of treatment. Significant differences compared with untreated control are indicated: *P < 0.05; **P < 0.01

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Interactive effect of curcumin and tumor necrosis factor-α-related apoptosis-inducing ligand on caspase activation

The effect of both curcumin and TRAIL alone and in combination on the activation of aspases 3, 8, and 9 were investigated in KCL-22 cells after incubation of 24 hours of treatment. As it is conceivable to see from the results, the activities of caspases 8 and 9 changed slightly in curcumin (50 μM) and TRAIL (25 ng/mL) alone and combination of both treated KCL-22 cell as compared to untreated cells [Figure 3] and [Figure 4]. However, a significant change in caspase-3 activity is shown in relative to control after 24 hours of incubation of KCL-22 cell with curcumin and TRAIL alone or in combination [Figure 5]. Thus, it is evident from the results that the treatment of curcumin and TRAIL alone has slight changes in the activity of caspases, whereas in combinatorial, their effect exerts significant change in caspases-3 activity.
Figure 3: Activation of Caspases-3, 8, and 9 in KCL22 cells with curcumin for 24 h. Each column shows the mean ± standard deviation of three experiments. Significant differences compared with untreated control are indicated by *P < 0.05

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Figure 4: Activation of caspases-3, 8, and 9 in KCL22 cells with tumor necrosis factor-α-related apoptosis-inducing ligand (25 ng/mL) for 24 h. Each column shows the mean ± standard deviation of three experiments. Significant differences compared with untreated control are indicated by *P < 0.05

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Figure 5: Activation of caspases-3, 8, and 9 in KCL22 cells with both curcumin (50 μM) and tumor necrosis factor-α-related apoptosis-inducing ligand (25 ng/mL) for 24 h. Each column shows the mean ± standard deviation of three experiments. Significant differences compared with untreated control are indicated by *P < 0.05

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Curcumin and tumor necrosis factor-α-related apoptosis-inducing ligand inhibit the IκB kinase activity via inhibiting its phosphorylation – A Western blot analysis

In nonactive cells, NFkB is sequestered in the cytoplasm with its inhibitory IκB subunit. Upon activation, NFkB dissociates from its IκB unit through phosphorylation by IκB Kinase (IKK) and translocates into the nucleus from cytoplasm. IB subunit was phosphorylated by IKK at its serine residues 32 and 36. Thus, the whole burden comes on the shoulders of IKK to phosphorylate IκB which in turn dissociates from the NFKB to make it free to translocate from cytoplasm to nucleus. Therefore, the aim of the study to investigate the inhibitory effect of curcumin and TRAIL is mediated through the alteration of phosphorylation of IKK. Our results showed that untreated cell and vehicle cell constitutively expressed phosphorylated IKK. Upon treatment of curcumin (50 μM) and TRAIL (25 ng/mL) alone, the phosphorylated IKK content decreased. Meanwhile, with cotreatment using both curcumin and TRAIL, the phosphorylated IKK content decreased drastically as compared to control and alone treatment of both agents [Figure 6].
Figure 6: Western blots for IκB Kinase inhibition by curcumin (50 μM) and tumor necrosis factor-α-related apoptosis-inducing ligand (25 ng/mL) after 24 h of treatment. Beta-actin was used as a loading control

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Curcumin and tumor necrosis factor-α-related apoptosis-inducing ligand induce apoptosis by inhibiting the nuclear factor kappa activity in KCL-22 cell

Transcription factor NFkB is an essential key regulator of several inflammatory responses. NFkB is found to be constitutively activated in a variety of cancers, including leukemia. Therefore, inhibition of NFkB is thought to provide therapeutic efficacy during cancer chemotherapy. In the previous Western blot experiment, we found that curcumin along with TRAIL provided excellent inhibitory effect on IKK activity. Therefore, in the present study, we aimed to investigate the efficacy of curcumin alone and in combination with TRAIL on NFkB activity to bind to its consensus oligonucleotide. It was found that upon treatment with curcumin (50 μM) and TRAIL (25 ng/mL) alone, the translocation of NFkB was a little inhibited in KCL-22 cells, but the translocation of NFkB was further inhibited upon combination of both curcumin (50 μM) and TRAIL (25ng/mL) [Figure 7].
Figure 7: Effect of KCL22 cells on translocation of NFkB after 24 h of treatment of curcumin (50 μM) and tumor necrosis factor-α-related apoptosis-inducing ligand (25 ng/mL)

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 > Discussion Top


Cancer, a leading cause of death in almost all countries, has been supposed to be caused due to defects in inflammatory pathways.[22] Acute inflammation increases the production of various inflammatory molecules, including ROS generation, cytokines, oncogenes, signaling pathway mediators, and transcriptional factors such as activator protein 1 and nuclear factor kB.

At present, herbal compound-based anticancer agents have been extensively used in clinical practice to combat the resistance against various chemotherapeutic agents. Most of the available anticancer drugs have limited efficacy are associated with severe side effects and are very expensive. Thus, identification of such pharmacological agents that do not have these disadvantages is required. Curcumin, derived from the rhizome of Curcuma longa plants, has been paid great interest by many scientists in the field of cancer over the past half-century. Strikingly, curcumin is a good alternative to current therapies as a result of its relatively safe profile, even at high doses. Because of its antioxidant, anti-inflammatory, and anticancer properties, curcumin is the best possible agent used against a variety of cancers.[23],[24] At present, much research has been focused on plant-derived dietary compounds against a variety of cancers and diseases.[25],[26]

Our results support previously reported studies on dietary supplements, including curcumin, being used in cancer treatments, suggesting that curcumin could exert anticancer effects on cancer cells.[27],[28]

Curcumin, as an anticancer agent, inhibits the growth of a variety of cancer cell lines, including breast cancer cell.[29],[30] Our results support the past investigations which detailed that curcumin induces its anticancer effects by inhibiting the proliferation and induction of apoptosis in the breast cancer cells.[31] Our studies demonstrated the effect of curcumin and TRAIL alone and in combination on the cell viability of KCL-22 cells by MTT assay. We observed that curcumin and TRAIL alone do not induce significant cell death as compared to the combination of both the agents at 24 h of treatment. Curcumin and TRAIL alone significantly reduce less cell viability at 24 h. On comparing, we found out that the cytotoxicity of both the agents on KCL-22 cells was much stronger than cytotoxicity of each agent alone. These findings are in support of previous studies where curcumin and TRAIL were additionally seen in the inhibition of prostate cancer cells.[32],[33] Thus, curcumin and TRAIL mediate the reduction of cell viability in time and dose-dependent manner. Our results indicate that curcumin and TRAIL both inhibit the KCL-22 cell growth by inducing apoptosis in time- and dose-dependent manner by decreasing the cell viability in KCL-22 cells.

Apoptosis is presently a subject of research of interest to a limited extent because cancer cells are defenseless to death by apoptosis by various chemotherapeutic drugs.[34] Chemoprevention is a promising procedure in light of the fact that different therapies are not effective in controlling various types of cancers. Initiation of apoptosis predominantly includes two signaling pathways distinguished by the initiator aspases: extrinsic or death receptor pathway includes caspases-8 and the intrinsic or mitochondrial pathway includes caspase-9 activation. Both the pathways trigger the activation of caspase-3. Caspase-3 has now been able to cleave a variety of substrates leading to the apoptosis of cancer cells.[35],[36],[37] Based on this evidence, we further investigate the role of different caspases in inducing apoptosis in KCL-22 cells.

In the present study, our results show that curcumin-induced apoptosis in KCL-22 cells was triggered by the activation of caspase. However, curcumin and TRAIL alone enhance little caspase-3 activity in KCL-22 cells relative to control cells. Moreover, curcumin and TRAIL both bring about a drastic change in caspase-3 activity as compared to curcumin and TRAIL alone. In addition, only a slight increase in caspase-8 and caspase-9 activation was seen in KCL-22 cells. This outcome could be supported due to the fact that caspase-8 and caspase-9 are thought to be in a critical initiating phase in apoptosis, while caspase-3 is associated with the effector phase of the apoptotic process.[38] Depending upon these results, we postulate that curcumin in combination of TRAIL induces apoptosis in KCL-22 cells through the activation of caspase-3. Several studies have shown that both curcumin and TRAIL in combination enhanced the caspase-3 and caspase-8 activities in the prostate cancer cells.[39] Our previous results suggest that curcumin and TRAIL-induced apoptosis through G2/M phase arrest cell cycle in KCL-22 myeloid cells. Thus, the results derived from all these experiments come in a direction that curcumin along with TRAIL underwent cell death in caspase-dependent manner.

NFkB, a ubiquitous transcription factor, regulates many genes responsible for cell survival, inflammation, carcinogenesis, and apoptosis.[40],[41] The constitutive activation of NFkB results in inhibition of chemotherapy-induced apoptosis in a number of cancer cells in vivo and in vitro.[42],[43] The outcome come to our study reveals that curcumin is a potent inhibitor of NFKB DNA binding and its nuclear translocation. Our study indicates that curcumin directly binds to the IKK, thereby blocks the IKK phosphorylation which in turn directly inhibits the IκB activity, which is a key step in NFkB activation and its translocation to the nucleus.[44]

It has been thought that IκB binds to the NFkB preventing its translocation from the cytoplasm to the nucleus. Upon activation by the stimulus, IKK kinases phosphorylate the inhibitory unit of IκB making NFkB free to translocate into the nucleus. Upon translocation into the nucleus, NFkB binds to its DNA-binding site to the operator which in turn transcribes the gene that makes the cell to keep on proliferating and evade apoptosis. In our study, we found that curcumin along with TRAIL has a pronounced effect on the inhibition of IKK kinase. However, curcumin and TRAIL alone have very less effect on IKK inhibition. Our study was in support of the previous study which states that curcumin can inhibit IKK activation, the kinase responsible for NFkB activation pathway.[45]

Curcumin as a chemopreventive agent sensitizes prostate cancer cells to TRAIL by inhibiting NFkB through IκBa phosphorylation suppression.[33] Curcumin inhibits NFkB-signaling pathways, making them to play key roles in cancer development and progression[46] Curcumin inhibits the IKK activity in colon cancer and macrophages.[47]

We also measured the level of inhibition of NFkB in the cytoplasm. The inhibition of NFkB by both curcumin and TRAIL was found to be 20–30 folds higher than what the each agent alone does. The inhibition of KCL-22 cell proliferation by curcumin and TRAIL is in agreement with previous reports that curcumin actuates the inhibition of NFkB, which leads to the inhibition of cellular proliferation of T-cell lymphomas[48] and AML cells.[49]

Cancers cells depend on oncogene addiction for maintenance of their phenotypes.[50] This overdependence can manage the decision of molecules-targeted therapies as inhibitors of “transcriptional pathways” like NFKB pathways can modulate cancer cells for apoptosis.[51] Therefore, the activation of NFkB is complex, given the myriad of signaling pathway and crosstalk associations which can fortify it. Thus, it is fundamental to search specific cancer cell pathway inhibitors to expand our knowledge for the selection of the best ever treatment. Systemic toxicity of various therapeutic agents is limited. Curcumin, which is a pharmacologically safe agent, gives a better alternate to deal with cancer cells resistant to TRAIL. Certain types of chemotherapeutic drugs like gemcitabine induce NFkB activation which leads to drugs resistance. Consolidated treatment with cytotoxic agents along with NFkB inhibitors may resolve this issue. However, alone NFkB inhibitors cannot eliminate cancer cells unless they are used with conjugation of some chemotherapeutic agents or radiations.[52] Combined therapy with cytotoxic agents may deliver synergistic impact on cancer cells, without or with less harm to the healthy cells. This study provides additional support for designing anti-inflammatory compounds which based on curcumin for diseases mediated through NFkB activation. Therefore, curcumin might have the prophylactic potential for the treatment of leukemias.


 > Conclusion Top


Our study provides clear evidence that curcumin along with TRAIL inhibits the cancer cell growth in CML cells KCL-22. Curcumin induces apoptosis in KCL-22 cells through the production of caspase-3 activity and the inhibition of NFkB activation. However, our study provides an additional knowledge to develop NFkB inhibitors in combination with curcumin for treatment of various cancers. All these results give an opportunity that the combination of both the agents, curcumin and TRAIL may contribute an effective therapeutic regimen against cancers.

Financial support and sponsorship

The above study was funded by Uttar Pradesh Council of Science and Technology (UPCST) Lucknow.

Conflicts of interest

There are no conflicts of interest.



 
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