Curcumin potentiates the anti-leukemia effects of imatinib by downregulation of the AKT/mTOR pathway and BCR/ABL gene expression in Ph+ acute lymphoblastic leukemia

Guo, Yong; Li, Yang; Shan, Qingqing; He, Guangcui; Lin, Juan; Gong, Yuping

doi:10.1016/j.biocel.2015.05.003

Cited by 40 publications

(17 citation statements)

References 36 publications

(37 reference statements)

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“…Our results reveal a significant apoptosis induction increment produced by chemotherapeutic drugs + curcumin compared to each individual agent. In agreement with our study, Guo et al (2015) reported an apoptosis increase using 1 µM imatinib + curcumin (25). However, they did not evaluate the drug dose and exposition time effect.…”

Section: Discussionsupporting

confidence: 84%

In�vitro effect of curcumin in combination with chemotherapy drugs in Ph+ acute lymphoblastic leukemia cells

et al. 2019

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Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), is characterized by the t(9;22)(q34q11) that generates the BCR-ABL protein with uncontrolled tyrosine kinase activity. Recently, a connection between BCR-ABL signaling with NF-κB activation mediated by CK2 has been hypothesized. Approximately 95% of patients with Ph + ALL have the BCR-ABLp190 isoform, which causes aggressive leukemia with a high rate of chemotherapy resistance. Therefore, the use of compounds that could improve the efficacy of chemotherapy drugs is of particular interest. Curcumin is an active chemical in turmeric with antineoplastic potential; it regulates protein-kinases by modulating downstream molecular pathways. The present study evaluated the effect of curcumin in combination with the chemotherapeutic drugs vincristine, imatinib and daunorubicin in the human OP-1 cell line. Several doses of the chemotherapy drugs were examined, and the effects were evaluated following 12, 24 and 48 h of exposure. The interaction between the chemotherapy drugs and curcumin was determined by the dose-effect curve, which generated a combination index (CI); these data were represented in isobolograms. In addition, the individual effect of each drug was compared with its effect in combination with curcumin on cell viability, apoptosis degree, NF-κB activation and gene expression changes. The present study observed that curcumin potentiates the efficacy of vincristine and imatinib, generating an additive/synergistic effect in a dose-and time-dependent manner. These combinations significantly increased the apoptosis degree, decreased the activation of NF-κB and the expression of its regulated genes. Conversely treatment with daunorubicin + curcumin combination produced an antagonistic/additive effect in a dose-dependent manner, and this combination significantly increased the apoptosis degree. However, this effect seems not to be associated with NF-κB activity, as no significant changes were observed in its activation or in the expression of the genes that it regulates. The results of the present study demonstrate that curcumin may be used as an adjuvant agent for chemotherapy in patients with Ph + ALL.

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Section: Discussionsupporting

confidence: 84%

In�vitro effect of curcumin in combination with chemotherapy drugs in Ph+ acute lymphoblastic leukemia cells

et al. 2019

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“…41 Previous research has demonstrated that the AKT/mTOR signaling pathway is critical to cell proliferation and that activation of this pathway is correlated with the incidence and progression of varying malignant tumors. 42,43 Some antitumor drugs can induce early autophagy and late apoptosis of tumor cells through the AKT/mTOR signaling pathway. 44,45 Activated AKT can activate Bcl-2 or Bcl-xl, suppress the release of cytochrome C, and inhibit caspase proteinase, thereby suppressing the incidence of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Norcantharidin Inhibits SK-N-SH Neuroblastoma Cell Growth by Induction of Autophagy and Apoptosis

Han

Wang

et al. 2016

Technol Cancer Res Treat

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Norcantharidin, a low-toxic analog of the active anticancer compound cantharidin in Mylabris, can inhibit proliferation and induce apoptosis of multiple types of cancer cells. However, the anticancer activities of norcantharidin with respect to neuroblastoma, and its underlying mechanisms, have not been investigated. Therefore, our study was designed to determine the efficacy of norcantharidin on SK-N-SH neuroblastoma cell death and to elucidate detailed mechanisms of activity. In the present study, norcantharidin suppressed the proliferation and cloning ability of SK-N-SH cells in a dose-dependent manner, apparently by reducing the mitochondrial membrane potential and arresting SK-N-SH cells at the G2/M stage, accompanied by elevated expressions of p21 and decreased expressions of cyclin B1 and cell division control 2. Treatment by norcantharidin induced significant mitophagy and autophagy, as demonstrated by a decrease in Translocase Of Outer Mitochondrial Membrane 20 (TOM20), increased beclin1 and LC3-II protein expression, reduced protein SQSTM1/p62 expression, and accumulation of punctate LC3 in the cytoplasm of SK-N-SH cells. In addition, norcantharidin induced apoptosis through regulating the expression of B-cell lymphoma 2-associated X protein/B-cell lymphoma 2 and B-cell lymphoma 2-associated X protein/myeloid cell leukemia 1 and activating caspase-3 and caspase-9-dependent endogenous mitochondrial pathways. We also observed an increase in phosphor-AMP-activated protein kinase accompanied with a decrease in phosphor-protein kinase B and mammalian target of rapamycin expression after treatment with norcantharidin. Subsequent studies indicated that norcantharidin participates in cellular autophagy and apoptosis via activation of the c-Jun NH2-terminal kinases/c-Jun pathway. In conclusion, our results demonstrate that norcantharidin can reduce the mitochondrial membrane potential, induce mitophagy, and subsequently arouse cellular autophagy and apoptosis; the AMP-activated protein kinase, protein kinase B/mammalian target of rapamycin, and c-Jun NH2-terminal kinases/c-Jun signaling pathways are widely involved in these processes. Thus, the traditional Chinese medicine norcantharidin could be a novel therapeutic strategy for treating neuroblastoma.

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“…The application of imatinib in K562 cells can inhibit the activity of the ERK and Akt kinase, and induce cell apoptosis through activating caspase-3. However, in some primary leukemia cells in the CML blastic phase, inhibiting the activity of the ERK and Akt kinase can induce caspase-3 mediated apoptosis, giving rise to the occurrence of resistance (30). In this study, we observed that upregulation of miRNA-301a significantly increased phosphorylation-ERK1/2 and decreased phosphorylation-AKT protein expression of K562 cell.…”

Section: Discussionmentioning

confidence: 48%

miRNA-301a induces apoptosis of chronic myelogenous leukemia cells by directly targeting TIMP2/ERK1/2 and AKT pathways

Huang

Lü

et al. 2016

Oncology Reports

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We investigated the biological functions and mechanism of miRNA‑301a on apoptosis in chronic myelogenous leukemia (CML). The expression of miRNA‑301a in patient with CML cells was higher than the expression of normal patients. Overall survival (OS) of chronic granulocytic leukemia cell patient with low miRNA‑301 expression was superior to that of CML patient with high miRNA‑301 expression. Moreover, the upregulation of miRNA‑301a increased cell proliferation, inhibited apoptosis and caspase-3 and -9 activity of K562 cells. Next, the upregulation of miRNA‑301a suppressed Bax/Bcl-2 rate and TIMP2 protein expression, increased phosphorylation-ERK1/2 and decreased phosphorylation-AKT protein expression of K562 cells. Furthermore, si‑TIMP2 expression enhanced the upregulation of miRNA‑301a on the promotion of cell proliferation, inhibition of apoptosis and caspase-3 and -9 activity, suppression of Bax/Bcl-2 rate, increasing phosphorylation-ERK1/2 and decreasing phosphorylation-AKT protein expression of K562 cells. Taken together, our results clearly suggested that miRNA‑301a induces apoptosis of CML cells by directly targeting the TIMP2/ERK1/2 and AKT pathways.

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Curcumin potentiates the anti-leukemia effects of imatinib by downregulation of the AKT/mTOR pathway and BCR/ABL gene expression in Ph+ acute lymphoblastic leukemia

Cited by 40 publications

References 36 publications

In�vitro effect of curcumin in combination with chemotherapy drugs in Ph+ acute lymphoblastic leukemia cells

In�vitro effect of curcumin in combination with chemotherapy drugs in Ph+ acute lymphoblastic leukemia cells

Norcantharidin Inhibits SK-N-SH Neuroblastoma Cell Growth by Induction of Autophagy and Apoptosis

miRNA-301a induces apoptosis of chronic myelogenous leukemia cells by directly targeting TIMP2/ERK1/2 and AKT pathways

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