Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 8  |  Page : 125-131

The autophagy induced by curcumin via MEK/ERK pathway plays an early anti-leukemia role in human Philadelphia chromosome-positive acute lymphoblastic leukemia SUP-B15 cells


1 Department of Hematology and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
2 Department of Hematology, Sichuan Provincial People's Hospital, Chengdu 610041, Sichuan Province, China

Date of Web Publication26-Mar-2018

Correspondence Address:
Ping Yu Gong
Department of Hematology and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, No. 37 Guo Xue Xiang, Chengdu 610041, Sichuan Province
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.172111

Rights and Permissions
 > Abstract 


Background: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is triggered by BCR/ABL tyrosine kinase which activates the downstream signaling pathways, such as Akt/mTOR, RAF/MEK/ERK, and STAT5 pathways. Curcumin has been shown to have inhibitory effects on cancers by inducing apoptosis and autophagy. We demonstrated that curcumin inhibited activation of Akt-mTOR, ABL/STAT5 pathways, inhibited cell proliferation, and induced apoptosis in Ph + ALL cells. Experiments here, were conducted to determine whether autophagy via MEK/ERK pathway involved in anti-leukemia effect of curcumin in Ph + ALL.
Materials and Methods: Ph + ALL cell line SUP-B15 was treated with curcumin. Cytotoxic activity of curcumin was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Signaling protein and specific maker of autophagy and conversion of LC3-I to LC3-II were determined by Western blot analysis. Cell apoptosis was determined by flow cytometry.
Results: Curcumin treatment up-regulated the activation of RAF/MEK/ERK at 4 h and 8 h after curcumin exposure in SUP-B15 cells, curcumin treatment induced autophagy at exactly 4 h and 8 h after curcumin exposure. Curcumin exerted cytotoxic activity against SUP-B15 cells at 4 h and 8 h, which was independent of apoptosis. MEK specific inhibitor U0126 inhibited the occurrence of autophagy, and then blocked curcumin-induced cytotoxicity at 4 h and 8 h.
Conclusions: Curcumin induce autophagic cell death in SUP-B15 cells via activating RAF/MEK/ERK pathway. These findings suggest that autophagic mechanism contribute to the curcumin-induced early SUP-B15 cell death, and autophagy is another anti-leukemia mechanism of curcumin.

Keywords: Autophagy, curcumin, Philadelphia chromosome-positive acute lymphoblastic leukemia, RAF/MEK/ERK


How to cite this article:
Guo Y, Shan QQ, Gong PY, Wang SC. The autophagy induced by curcumin via MEK/ERK pathway plays an early anti-leukemia role in human Philadelphia chromosome-positive acute lymphoblastic leukemia SUP-B15 cells. J Can Res Ther 2018;14:125-31

How to cite this URL:
Guo Y, Shan QQ, Gong PY, Wang SC. The autophagy induced by curcumin via MEK/ERK pathway plays an early anti-leukemia role in human Philadelphia chromosome-positive acute lymphoblastic leukemia SUP-B15 cells. J Can Res Ther [serial online] 2018 [cited 2018 Dec 12];14:125-31. Available from: http://www.cancerjournal.net/text.asp?2018/14/8/125/172111




 > Introduction Top


The Philadelphia (Ph) chromosome is the most frequent genetic aberration in acute lymphoblastic leukemia (ALL), especially in adult ALL patients, and it is associated with a dismal prognosis.[1],[2],[3] The reciprocal translocation, t (9;22), generates a bcr/abl fusion gene which encodes the BCR/ABL fusion protein with constitutively active tyrosine kinase activity.[4] BCR/ABL kinase controls the proliferation, differentiation, and apoptosis of lymphoid precursors by activating the downstream signaling pathways such as Akt/mTOR, RAF/MEK/ERK, and STAT5 pathways.[5],[6] In the preimatinib era, the Ph + ALL prognosis was poor, with 5-year overall survival rates of 10–20%.[7] The tyrosine kinase inhibitor, imatinib, down-regulates BCR/ABL activity and is widely used to treat Ph + leukemia, including chronic myeloid leukemia and Ph + ALL.[8],[9],[10] However, the response of Ph + ALL to imatinib monotherapy is low, the response duration is short, and relapses are continuing problems.[11],[12] To further improve the clinical outcome and provide therapeutic options for Ph + ALL patients, other investigational therapy should be developed.

Curcumin, a yellow polyphenol, is the principle active compound of the perennial herb, Curcuma longa. Curcumin has been attributed to various properties including, anti-inflammatory, antioxidant, anti-angiogenic, anti-proliferative, and anti-tumor.[13],[14] Curcumin has been shown to be a multi-targeted agent, whose targets includes inflammatory cytokines, growth factors, adhesion molecules, anti-apoptotic proteins, transcription factors, and protein kinases linked with cell survival and proliferation.[15] Multi-target property of curcumin brings up its broad-spectrum anti-tumor activity. Many studies have suggested anti-tumor efficiency of curcumin in a wide array of cancer cell types.[16] The main anti-tumor mechanism of curcumin is inducing apoptotic cell death, however, the exact mechanisms of curcumin-induced cell death still remain ill-defined. Recently, curcumin has been reported to induce autophagic cell death in malignant cells. Kim et al. reported that curcumin showed anticancer activity against oral squamous cell carcinoma via both autophagy and apoptosis.[17] Yamauchi et al. found curcumin suppressed the growth of mesothelioma cells by inducing autophagy.[18] Wu et al. demonstrated that tetrahydrocurcumin, a major metabolite of curcumin, induced autophagic cell death in human leukemia-60 cells via modulation of PI3K/Akt-mTOR and MAPK signaling pathways.[19] Lee et al. found curcumin-induced autophagic cell death in HCT116 human colon cancer cells via leading to reactive oxygen species production.[20] Aoki et al. reported curcumin suppressed the growth of malignant gliomas in vitro and in vivo through induction of autophagy.[21] O'Sullivan-Coyne et al. demonstrated that curcumin-induced autophagic cell death in esophageal cancer cells.[22] From above published literatures, it can be seen that inducing autophagic cell death is another important anti-cancer mechanism of curcumin.

We previously demonstrated that ABL kinase and its downstream Akt/mTOR, RAF/MEK/ERK, and STAT5 signaling pathways were constitutively active in human Ph + ALL SUP-B15 cells. We found curcumin inhibited the activation of Akt/mTOR, ABL/STAT5 signaling pathways, and activating apoptosis at 24 h after curcumin treatment. However, curcumin had no inhibitory effect on RAF/MEK/ERK pathway, on the contrary, curcumin up-regulated the activation of RAF/MEK/ERK in the early stage of exposure, especially at 4 h and 8 h. A few previous studies reported that RAF/MEK/ERK pathway facilitate autophagy.[21],[23],[24],[25],[26] Whether or not curcumin-induced activation of RAF/MEK/ERK pathway induce autophagy and then contribute to the cytotoxicity of curcumin against SUP-B15 cells, remain unclear. In this study, we investigated whether or not curcumin induce autophagic cell death via activating RAF/MEK/ERK pathway.


 > Materials and Methods Top


Materials

Curcumin was purchased from Sigma. The 100-mM DMSO stock solution of curcumin was stored at −20°C. The phosphospecific antibodies against cRAF (ser338), MEK1/2 (ser217/221), ERK1/2 (Thr202/Tyr204), and the antibodies against LC3 were obtained from Cell Signaling Technologies. MEK inhibitor U0126 was obtained from Cell Signaling Technologies. The annexin V-FITC apoptosis detection kit was obtained from KeyGen Biotech. Co., Ltd., 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) was obtained from Sigma. Iscove's modified Dulbecco's medium (IMDM) medium, penicillin/streptomycin, and fetal bovine serum (FBS) were obtained from Hyclo company.

Cell lines and culture conditions

Ph + ALL SUP-B15 cells expressing P190-BCR/ABL protein were purchased from American Type Culture Collection (ATCC, Rockville, MD, USA). The cells were cultured in IMDM medium containing 10% FBS, 100 U/ml penicillin and 100 g/ml streptomycin, and in 5% CO2 incubator at 37°C.

Cytotoxic assays

Cytotoxicity of curcumin on SUP-B15 cells was measured with an MTT assay. Briefly, the cells were incubated for the indicated time at 37°C in triplicate in a 96 well-plate in the presence or absence of curcumin in a final volume of 100 μl. Thereafter, 20 μl of MTT solution, of concentration 5 mg/ml in phosphate-buffered solution (PBS), was added to each well. After 4 h of incubation at 37°C, 100 μl of sodium dodecyl sulfate (SDS)-isobutanol-HCl solution was added, and incubation was continued overnight at room temperature. Subsequently, the optical density (OD) was measured using μQuant MQX200 microplate spectrophotometer (Biotek) at a wavelength of 570 nm. The cell cytotoxicity was displayed as a percentage according to the following formula: (%) = OD (control) − OD (experiment samples)/(OD[control] − OD[blank]) ×100%.

Apoptosis analysis

The cells were treated with curcumin for indicated time, and 2 × 105 cells were harvested, washed with PBS, and re-suspended in 100 μl of binding buffer. Then, 5 μl of Annexin V-FITC was added, and 5 μl of PI was added after 10 min. Then the cells were incubated at room temperature for 15 min in the dark and 400 μl of binding buffer was added, and the stained cells were analyzed using a Cytomics FC500 flow cytometer equipped with CXP software. For each analysis, 10,000 events were recorded.

Western blot analysis

Whole cell extracts were prepared in RAPI lysis buffer and the protein extracts were quantitated and loaded onto a 10–15% SDS-polyacrylamide gel. After electrophoresis, the proteins were electro-transferred to a nitrocellulose membrane. The membrane was incubated with primary antibody, washed and incubated with horseradish peroxidase-conjugated secondary antibody, and finally, the signals were detected using the enhanced chemiluminescence detection system and film (Bio-Rad Laboratories Inc., CA, USA), according to the manufacturer's instructions.

Statistical analysis

Cell cytotoxicity, ratio of LC3-II/LC3-I, and apoptosis percent were analyzed with a one-way ANOVA and independent sample t-test. P < 0.05 was considered as statistically significant. Asterisks indicate the level of significance. All of the statistical analyses were performed using the software SPSS 16.0 for windows.


 > Results Top


Curcumin induces autophagy in the early stages of exposure in SUP-B15 cells

Our study demonstrated that curcumin inhibited the proliferation of SUP-B15 cells, and the IC50 of curcumin at 72 h was 27.59 ± 7.06 μM. So, we selected 30 μM as working concentration of curcumin. Our data had shown that curcumin inhibited the activation of ABL, STAT5a kinase, and Akt/mTOR signaling in a time-dependent manner [Figure 1]a, while curcumin up-regulated the activation of RAF/MEK/ERK at 4 h and 8 h after curcumin exposure, thereafter, the level of activation of RAF/MEK/ERK declined gradually near base line at 24 h [Figure 1]b. The aim of the present study is to investigate whether or not curcumin induce autophagy via activating RAF/MEK/ERK. First, we investigated whether or not curcumin induce autophagy. According to the conversion of LC3-I to LC3-II is a specific maker of autophagy, we detected the expression of LC3-I and LC3-II by Western blotting assay, the ratio of LC3-II/LC3-I was calculated by densitometric analyses. As shown in [Figure 1]c and [Figure 1]d, curcumin-induced increase of LC3-II: LC3-I ratio occurred at 4 h and peaked at 8 h. The ratio of LC3-II to LC3-I increased from 3.25 ± 0.52 (control) to 5.88 ± 0.41 at 4 h, 7.86 ± 0.51 at 8 h, respectively, then declined to 4.24 ± 0.46 at 24 h, which suggested curcumin-induced autophagy mainly occurred at 4 h and 8 h.
Figure 1: Curcumin up-regulated the activation of RAF/MEK/ERK pathway and induced autophagy in SUP-B15 cells. SUP-B15 cells were treated with 30 μM curcumin for 4h, 8h, and 24 h, respectively. Cells were then harvested and total proteins were extracted. Equal amounts of proteins were separated on a 10–15% sodium dodecyl sulfate-polyacrylamide gel electrophoresis gel and immunoblotted with the indicated antibodies. GAPDH was used as a loading control. Representative Western blots and densitometric analyses (expressed as relative value of control) are shown. (a) Curcumin treatment inhibited the activation of ABL, STAT5a, and Akt/mTOR signaling in a time-dependent manner. (b) Curcumin treatment up-regulated the activation of RAF/MEK/ERK pathway at 4 h and 8 h. (c) Curcumin treatment induced the occurrence of autophagy at 4 h and 8 h. (d) Curcumin treatment induced an increase of ratio of LC3-II to LC3-I, the values were obtained in three independent experiments and were represented as means ± standard error. *Represents significant difference (P < 0.05)

Click here to view


The autophagy induced by curcumin is mediated via activating RAF/MEK/ERK pathway

Considering that the time frame of the occurrence of autophagy and the activation of RAF/MEK/ERK is so consistent, we daringly hypothesized that curcumin induced autophagy via activating RAF/MEK/ERK pathway. To confirm our hypothesis, we adopted MEK specific inhibitor U0126. As shown in [Figure 2]a, the activation of ERK1/2 at 4 h and 8 h was blocked by pretreating SUP-B15 cells with 10 μM U0126 for 1 h before curcumin treatment, consequently, curcumin-induced increase of ratio of LC3-II/LC3-I disappeared [Figure 2]b and [Figure 2]c, which indicated that MEK inhibitor inhibited the occurrence of curcumin-induced autophagy. Thus, curcumin-induced autophagy by activating RAF/MEK/ERK pathway was testified.
Figure 2: Effect of MEK inhibitor U0126 on curcumin-mediated activation of RAF/MEK/ERK pathway and autophagy. SUP-B15 cells were incubated at 37°C with 10 μM U0126 for 1 h, then incubated with 30 μM curcumin for 4 h, 8 h, and 24 h. At the end of incubation, total proteins were extracted and RAF/MEK/ERK signaling proteins and LC3 were examined by Western blot analysis with indicated antibodies. (a) U0126 inhibited curcumin-induced activation of ERK signaling. (b) U0126 inhibited curcumin-induced autophagy. (c) U0126 inhibited curcumin-mediated increase of ratio of LC3-II to LC3-I, the values were obtained in three independent experiments and were represented as means ± standard deviation. *Represents significant difference (P < 0.05). NS represents no significant difference

Click here to view


The autophagy induced by curcumin contributed to inhibit the growth of SUP-B15 cells

Autophagy is a double-edged sword, it might contribute to promote the survival of cancer cells, or inhibit their growth. It is unclear whether curcumin-induced autophagy is to promote or inhibit the growth of SUP-B15 cell. Therefore, we used MTT assay to examine whether 30 μM curcumin has cytotoxic activity against SUP-B15 cells or promote the cell growth at 4 h and 8 h. As shown [Figure 3], curcumin had indeed cytotoxic activity against SUP-B15 cells at 4 h, 8 h, and inhibition rates of curcumin at 4 h, 8 h was 13.69 ± 6.36%, 23.11 ± 9.33%, respectively.
Figure 3: Cytotoxicity of curcumin against SUP-B15 cells at 4 h and 8 h after exposure. SUP-B15 cells (2 × 106 cells/ml) were incubated at 37°C with 30 μM curcumin for 4 h, 8 h, and 24 h. Cell viability were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide method. The results are shown as the mean ± standard deviation of triplicates

Click here to view


The cytotoxic effect of curcumin on SUP-B15 cell in the early stages of exposure is independent of apoptosis

Inducing tumor cells apoptosis is the main anti-tumor mechanism of curcumin. To explore the role of apoptosis in curcumin-induced cytotoxicity at 4 h and 8 h, we next investigated the apoptosis rates by flow cytometry at this time point. As shown in [Figure 4], apoptosis rates at 4 h, 8 h were 5.70 ± 0.5%, 7.27 ± 1.03%, respectively, there was no significant difference from the control group in which apoptosis rate was 4.83 ± 0.40%. However, apoptosis rates significantly increased and reached 53.23 ± 4.07% at 24 h. These results showed that curcumin-induced cytotoxicity at 4 h and 8 h were independent of apoptosis. Ruling out the role of apoptosis, we presumed that curcumin-induced cytotoxicity at 4 h and 8 h was mediated by autophagy.
Figure 4: Curcumin-induced cytotoxicity against SUP-B15 cells at 4 h and 8 h was independent of apoptosis. SUP-B15 cells (2 × 105 cells/ml) were incubated at 37°C with 30 μM curcumin for 4 h, 8 h, and 24 h. The percent of apoptotic cells was examined by flow cytometry using the Annexin V-FITC/PI apoptosis detection kit. Data were obtained from three independent experiments and expressed as mean ± standard deviation. **Represents significant difference (P < 0.01). NS represents no significant difference

Click here to view


Curcumin-induced SUP-B15 cells death in the early stages of exposure is dependent of autophagy

We used specific MEK inhibitor U0126 to further confirm that the cytotoxicity induced by curcumin at 4 h and 8 h was mediated by autophagy. As shown in [Figure 5], when SUP-B15 cells were pretreated with 10 μM U0126 for 1 h before the curcumin exposure, the curcumin-induced inhibition rates at 4 h and 8 h declined from 13.69 ± 6.36%, 23.11 ± 9.33% to 2.53 ± 1.52%, 4.73 ± 2.82%, respectively. It has been confirmed above that MEK inhibitor blocked curcumin-induced cytotoxicity by inhibiting the occurrence of autophagy. From this point, we concluded that curcumin-induced cytotoxicity at 4 h and 8 h is mediated via autophagy.
Figure 5: Effect of MEK inhibitor U0126 on curcumin-induced cytotoxicity against SUP-B15 cells at 4 h and 8 h. SUP-B15 cells (2 × 106 cells/ml) were incubated at 37°C with 10 μM U0126 for 1 h, then incubated with 30 μM curcumin for 4 h, 8 h, and 24 h. Cell viability was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide method. The results are shown as the mean ± standard deviation of triplicates. *Represents significant difference (P < 0.05)

Click here to view



 > Discussion Top


Although the anticancer activity of curcumin has been identified in many tumor cells and inducing malignant cell apoptotic cell death is the main anti-tumor mechanism of curcumin, the exact mechanisms of curcumin-induced malignant cell death still remain ill-defined. Recently, curcumin has been reported to induce autophagic cell death in malignant cells. Akt/mTOR and RAF/MEK/ERK signaling pathways are frequently associated with the regulation of autophagy, and activation of RAF/MEK/ERK pathway is used to facilitate autophagy.[21],[23],[24],[25],[26] In our study, we found that curcumin-induced Ph + ALL SUP-B15 cells apoptosis and inhibited proliferation via down-regulating the activation of ABL, STAT5, and Akt-mTOR signaling pathways after 24 h exposure. As for constitutively active RAF/MEK/ERK pathway in SUP-B15 cells, curcumin had no inhibitory effect on it. On the contrary, curcumin up-regulated its activation at 4 h and 8 h after exposure to curcumin. The role of the curcumin-mediated activation of RAF/MEK/ERK pathway in anti-leukemia efficiency of curcumin on Ph + ALL is unclear, which promotes us to unveil its underlying role in anti-leukemia mechanism of curcumin in Ph + ALL. Based on published literatures that activation of RAF/MEK/ERK pathway facilitates autophagy, we aimed to investigate the relationship between activation of RAF/MEK/ERK pathway, autophagy, and anti-leukemia activity of curcumin in Ph + ALL cell line SUP-B15 cells in the present study. To this end, we first used Western blotting assay to examine whether or not curcumin induce autophagy. Our results demonstrated that curcumin indeed induced the occurrence of autophagy in SUP-B15 cells at exact 4 h and 8 h after curcumin exposure. Considering the time frame of the occurrence of autophagy and the activation of RAF/MEK/ERK is so consistent, we presumed that there must be some links between RAF/MEK/ERK pathway and autophagy in SUP-B15 cells. Based on our finding and these literatures which have suggested RAF/MEK/ERK pathway facilitate autophagy, we daringly hypothesized that curcumin-induced autophagy via activating RAF/MEK/ERK pathway. To confirm our hypothesis, we next investigated the effect of MEK specific inhibitor U0126 on curcumin-induced autophagy. Consequently, U0126 inhibited curcumin-induced autophagy by blocking the activation of RAF/MEK/ERK signaling pathway. Thus, we verified that autophagy induced by curcumin was via activating RAF/MEK/ERK pathway in SUP-B15 cells.

Autophagy acts as a double-edged sword in health and disease, and its role in cancer is a controversial issue.[27] Some reports suggest that autophagy promotes survival of cancer cell,[28],[29] in contrast, there are evidences that autophagy is associated with cancer suppression.[30],[31],[32] It is unclear that whether curcumin-induced autophagy is to promote Ph + ALL cells growth or inhibit them. To reveal the role of curcumin-induced autophagy in its anti-leukemia activity, we first examined whether curcumin had cytotoxic activity against SUP-B15 cells at 4 h and 8 h by MTT assay. Our results demonstrated that the treatment of curcumin for 4 h and 8 h had indeed cytotoxic activity against SUP-B15 cells, and cytotoxicity at 4 h was more significant than that at 4 h, which was consistent with the occurrence of autophagy. Next, using flow cytometry, we verified that curcumin-induced cytotoxicity at 4 h and 8 h was independent of apoptosis. To further confirm the role of autophagy in anti-leukemia of curcumin, we used MEK specific inhibitor U0126 once more. SUP-B15 cells were pretreated with 10 μM U0126 for 1 h, cytotoxicity of curcumin against SUP-B15 cells was examined by MTT methods. Our data demonstrated that U0126 declined curcumin-induced cytotoxicity at 4 h and 8 h. As described previously, curcumin-induced cytotoxicity at 4 h and 8 h was inhibited by U0126 via blocking the occurrence of autophagy. Therefore, we concluded that curcumin-mediated autophagy was lethal to Ph + ALL cells and contributed to the anti-leukemia activity of curcumin.

Akt/mTOR is another pathway that regulate autophagy.[26] Because there is no significant relationship in time point between the occurrence of curcumin-induced autophagy and inhibition of Akt/mTOR pathway in SUP-B15 cells, thus we speculated that the role of Akt/mTOR pathway in autophagy is weaker than RAF/MEK/ERK pathway.

In summary, we showed here for the first time that curcumin induces autophagy in Ph + ALL cells in vitro. ERK1/2 pathway is involved in curcumin-induced autophagy. Curcumin-induced autophagy contributes to its anti-leukemia efficacy at early stage after exposure in the SUP-B15 cells. Besides apoptosis, inducing autophagy is another anti-leukemia mechanism of curcumin in Ph + ALL.

Financial support and sponsorship

National Natural Science Foundation of China (No.81400123), Foundation of the Science and Technology Department of Sichuan Province (No. 2013SZ0025).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Piccaluga PP, Martinelli G, Rondoni M, Visani G, Baccarani M. Advances and potential treatment for Philadelphia chromosome-positive adult acute lymphoid leukaemia. Expert Opin Biol Ther 2006;6:1011-22.  Back to cited text no. 1
[PUBMED]    
2.
Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med 2006;354:166-78.  Back to cited text no. 2
[PUBMED]    
3.
Moorman AV, Harrison CJ, Buck GA, Richards SM, Secker-Walker LM, Martineau M, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): Analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood 2007;109:3189-97.  Back to cited text no. 3
[PUBMED]    
4.
Faderl S, Jeha S, Kantarjian HM. The biology and therapy of adult acute lymphoblastic leukemia. Cancer 2003;98:1337-54.  Back to cited text no. 4
[PUBMED]    
5.
Sawyers CL. Signal transduction pathways involved in BCR-ABL transformation. Baillieres Clin Haematol 1997;10:223-31.  Back to cited text no. 5
[PUBMED]    
6.
Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK, et al. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J 1997;16:6151-61.  Back to cited text no. 6
[PUBMED]    
7.
Dombret H, Gabert J, Boiron JM, Rigal-Huguet F, Blaise D, Thomas X, et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia – Results of the prospective multicenter LALA-94 trial. Blood 2002;100:2357-66.  Back to cited text no. 7
[PUBMED]    
8.
Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009;23:1054-61.  Back to cited text no. 8
    
9.
Gruber F, Mustjoki S, Porkka K. Impact of tyrosine kinase inhibitors on patient outcomes in Philadelphia chromosome-positive acute lymphoblastic leukaemia. Br J Haematol 2009;145:581-97.  Back to cited text no. 9
[PUBMED]    
10.
Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: A children's oncology group study. J Clin Oncol 2009;27:5175-81.  Back to cited text no. 10
[PUBMED]    
11.
Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001;344:1038-42.  Back to cited text no. 11
[PUBMED]    
12.
Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT, et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 2002;100:1965-71.  Back to cited text no. 12
[PUBMED]    
13.
Sharma RA, Gescher AJ, Steward WP. Curcumin: The story so far. Eur J Cancer 2005;41:1955-68.  Back to cited text no. 13
    
14.
Karunagaran D, Rashmi R, Kumar TR. Induction of apoptosis by curcumin and its implications for cancer therapy. Curr Cancer Drug Targets 2005;5:117-29.  Back to cited text no. 14
[PUBMED]    
15.
Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett 2008;269:199-225.  Back to cited text no. 15
[PUBMED]    
16.
Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: Preclinical and clinical studies. Anticancer Res 2003;23:363-98.  Back to cited text no. 16
    
17.
Kim JY, Cho TJ, Woo BH, Choi KU, Lee CH, Ryu MH, et al. Curcumin-induced autophagy contributes to the decreased survival of oral cancer cells. Arch Oral Biol 2012;57:1018-25.  Back to cited text no. 17
[PUBMED]    
18.
Yamauchi Y, Izumi Y, Asakura K, Hayashi Y, Nomori H. Curcumin induces autophagy in ACC-MESO-1 cells. Phytother Res 2012;26:1779-83.  Back to cited text no. 18
[PUBMED]    
19.
Wu JC, Lai CS, Badmaev V, Nagabhushanam K, Ho CT, Pan MH. Tetrahydrocurcumin, a major metabolite of curcumin, induced autophagic cell death through coordinative modulation of PI3K/Akt-mTOR and MAPK signaling pathways in human leukemia HL-60 cells. Mol Nutr Food Res 2011;55:1646-54.  Back to cited text no. 19
[PUBMED]    
20.
Lee YJ, Kim NY, Suh YA, Lee C. Involvement of ROS in curcumin-induced autophagic cell death. Korean J Physiol Pharmacol 2011;15:1-7.  Back to cited text no. 20
[PUBMED]    
21.
Aoki H, Takada Y, Kondo S, Sawaya R, Aggarwal BB, Kondo Y. Evidence that curcumin suppresses the growth of malignant gliomasin vitro andin vivo through induction of autophagy: Role of Akt and extracellular signal-regulated kinase signaling pathways. Mol Pharmacol 2007;72:29-39.  Back to cited text no. 21
[PUBMED]    
22.
O'Sullivan-Coyne G, O'Sullivan GC, O'Donovan TR, Piwocka K, McKenna SL. Curcumin induces apoptosis-independent death in oesophageal cancer cells. Br J Cancer 2009;101:1585-95.  Back to cited text no. 22
    
23.
Ogier-Denis E, Pattingre S, El Benna J, Codogno P. Erk1/2-dependent phosphorylation of Galpha-interacting protein stimulates its GTPase accelerating activity and autophagy in human colon cancer cells. J Biol Chem 2000;275:39090-5.  Back to cited text no. 23
[PUBMED]    
24.
Pattingre S, Bauvy C, Codogno P. Amino acids interfere with the ERK1/2-dependent control of macroautophagy by controlling the activation of Raf-1 in human colon cancer HT-29 cells. J Biol Chem 2003;278:16667-74.  Back to cited text no. 24
[PUBMED]    
25.
Li B, Takeda T, Tsuiji K, Wong TF, Tadakawa M, Kondo A, et al. Curcumin induces cross-regulation between autophagy and apoptosis in uterine leiomyosarcoma cells. Int J Gynecol Cancer 2013;23:803-8.  Back to cited text no. 25
[PUBMED]    
26.
Ellington AA, Berhow MA, Singletary KW. Inhibition of Akt signaling and enhanced ERK1/2 activity are involved in induction of macroautophagy by triterpenoid B-group soyasaponins in colon cancer cells. Carcinogenesis 2006;27:298-306.  Back to cited text no. 26
[PUBMED]    
27.
Shintani T, Klionsky DJ. Autophagy in health and disease: A double-edged sword. Science 2004;306:990-5.  Back to cited text no. 27
[PUBMED]    
28.
Eskelinen EL. Doctor Jekyll and Mister Hyde: Autophagy can promote both cell survival and cell death. Cell Death Differ 2005;12 Suppl 2:1468-72.  Back to cited text no. 28
[PUBMED]    
29.
Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer 2007;7:961-7.  Back to cited text no. 29
[PUBMED]    
30.
Gozuacik D, Kimchi A. Autophagy as a cell death and tumor suppressor mechanism. Oncogene 2004;23:2891-906.  Back to cited text no. 30
[PUBMED]    
31.
Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev 2007;21:1367-81.  Back to cited text no. 31
[PUBMED]    
32.
Guillon-Munos A, van Bemmelen MX, Clarke PG. Autophagy can be a killer even in apoptosis-competent cells. Autophagy 2006;2:140-2.  Back to cited text no. 32
[PUBMED]    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Materials and Me...>Results>Discussion>Article Figures
  In this article
>References

 Article Access Statistics
    Viewed2160    
    Printed85    
    Emailed0    
    PDF Downloaded107    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]