Suppression of human lung cancer cell growth and migration by berbamine

Duan, Huiying; Luan, Jinling; Liu, Qian; Yagasaki, Kazumi; Zhang, Guoying

doi:10.1007/s10616-009-9240-x

Cited by 31 publications

(17 citation statements)

References 19 publications

(19 reference statements)

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“…We found that ␤-catenin and Stat3 were present in a protein complex immunoprecipitated by the CaMKII ␥ antibody (Figure 7E-F). These findings, together with previous studies, 25,26 unravel that CaMKII ␥ is a critical molecular switch which could activate multiple LSC-related signaling networks including Wnt/␤-catenin, Stat3, and NF-B pathways.…”

Section: Camkii ␥ Is a Critical Target Of Berbamine For Its Antileukesupporting

confidence: 70%

“…At the cellular level, berbamine exhibits significantly antiproliferative activities of a variety of leukemia, [17][18][19][20][21] lymphoma, 22 multiple myeloma, 23 and solid tumor cell lines. [24][25][26][27] At the molecular level, berbamine-mediated antitumor activity was shown to be involved in PI3K/Akt, 22 nuclear factor kappaB, 23 Fas-mediated apoptosis, 26 calmodulin, 28,29 phospholipase A2, 16,30,31 P-glycoprotein, 24 and telomerase activity. 32 A previous study showed that compound E6, an analog of berbamine, can inhibit calmodulin-dependent myosin light chain kinase (MLCK) activity through affecting calmodulin (CaM) but not MLCK.…”

Section: Introductionmentioning

confidence: 99%

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CaMKII γ, a critical regulator of CML stem/progenitor cells, is a target of the natural product berbamine

Chen

Meng³

et al. 2012

Blood

106

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Bcr-Abl tyrosine kinase inhibitors (TKIs) have been a remarkable success for the treatment of Ph ؉ chronic myeloid leukemia (CML). However, a significant proportion of patients treated with TKIs develop resistance because of leukemia stem cells (LSCs) and T315I mutant Bcr-Abl. Here we describe the unknown activity of the natural product berbamine that efficiently eradicates LSCs and T315I mutant BcrAbl clones. Unexpectedly, we identify CaMKII ␥ as a specific and critical target of berbamine for its antileukemia activity. Berbamine specifically binds to the ATPbinding pocket of CaMKII ␥, inhibits its phosphorylation and triggers apoptosis of leukemia cells. More importantly, CaMKII ␥ is highly activated in LSCs but not in normal hematopoietic stem cells and coactivates LSC-related ␤-catenin and Stat3 signaling networks. The identification of CaMKII ␥ as a specific target of berbamine and as a critical molecular switch regulating multiple LSC-related signaling pathways can explain the unique antileukemia activity of berbamine. These findings also suggest that berbamine may be the first ATP-competitive inhibitor of CaMKII ␥, and potentially, can serve as a new type of molecular targeted agent through inhibition of the CaMKII ␥ activity for treatment of leukemia. (Blood. 2012; 120(24):4829-4839) IntroductionChronic myeloid leukemia (CML), which accounts for approximately 20% of all adult leukemias, 1 is characterized by the presence of the Philadelphia chromosome (Ph ϩ ), which results from a chromosomal translocation between the Bcr gene on chromosome 22 and the Abl gene on chromosome 9. 2 This translocation produces the fusion protein Bcr-Abl that has constitutive kinase activity 3 and is essential for the growth of CML cells and has become an attractive target for treatment of Ph ϩ CML cases, and the Abl tyrosine kinase inhibitors (TKIs) are now first-line therapeutic agents. [4][5][6] Inhibition of Bcr-Abl with Abl tyrosine kinase inhibitors (TKIs), such as imatinib (IM), is highly effective in controlling CML at chronic phase but not curing the disease. This is largely because of the inability of these kinase inhibitors to kill leukemia stem cells (LSCs) responsible for initiation, drug resistance, and relapse of CML 4-6 and Bcr-Abl gene mutation, particularly T315I mutant Bcr-Abl clones. 7-9 Thus, drug resistance associated with TKIs has created a need for more potent and safer therapies against other targets apart from the Bcr-Abl oncogenic kinase.Increasing evidence shows that traditional Chinese medicine (TCM) products not only play important roles in the discovery and development of drugs, but can also be used as molecular probes for identifying therapeutic targets. Homoharringtonine, arsenic trioxide, and triptolide are 3 famous examples. 9-11 Berbamine (BBM) is a structurally unique bisbenzylisoquinoline isolated from TCM Berberis amurensis, and has been used in traditional Chinese medicine for treating a variety of diseases from inflammation to tumors for many years. 12,13 It possesses a unique profile ...

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Section: Camkii ␥ Is a Critical Target Of Berbamine For Its Antileukesupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

CaMKII γ, a critical regulator of CML stem/progenitor cells, is a target of the natural product berbamine

Chen

Meng³

et al. 2012

Blood

106

View full text Add to dashboard Cite

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“…The detailed procedures were followed accordingly (Duan et al 2009). In brief, hepatoma cells at 70% confluence were treated for 48 h with perifosine at concentrations of 0 (DMSO, vehicle as control) and 10 lmol/L, respectively.…”

Section: Morphological Evaluation Of Apoptotic Cellsmentioning

confidence: 99%

Perifosine induces cell cycle arrest and apoptosis in human hepatocellular carcinoma cell lines by blockade of Akt phosphorylation

et al. 2010

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Hepatocellular carcinoma (HCC) is one of the most common solid cancers, representing the third cause of cancer-related death among cirrhotic patients. Treatment of advanced HCC has become a very active area of research. Perifosine, a new synthetic alkylphospholipid Akt inhibitor, has shown anti-tumor activity by inhibition of Akt phosphorylation. In this study, the effect of perifosine on the cell proliferation and apoptosis in hepatoma cells has been investigated. Cell growth inhibition was detected by MTT assay, cell cycle was analyzed by flow cytometry, AnnexinV-FITC apoptosis detection kit was used to detect cell apoptosis, and protein expression was examined by Western blotting analysis. Our present studies showed that Akt phosphorylation was inhibited by perifosine in HepG2 and Bel-7402 human hepatocellular carcinoma cells. Perifosine inhibited the growth of HepG2 cells and Bel-7402 cells in a dose-dependent manner, and arrested cell cycle progression at the G(2) phase. Apoptosis induction became more effective with increasing perifosine concentration. The caspase cascade and its downstream effectors, Poly (ADP-ribose) polymerase (PARP), were also activated simultaneously upon perifosine treatment. The proapoptotic effect of perifosine was in part depending on regulation of the phosphorylation level of ERK and JNK. Perifosine cotreatment substantially increased cytotoxic effects of cisplatin in HepG2 cells. Down-regulating the expression of Bcl-2 and up-regulating the level of Bax may be the potential mechanism for this synergistic effect. Our findings suggest that the small molecule Akt inhibitor perifosine shows substantial anti-tumor activity in human hepatoma cancer cell lines, and is a good candidate for treatment combinations with classical cytostatic compounds in hepatocellular carcinoma.

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“…The balance between these two groups plays a critical role in regulating cell growth and controlling mitochondrial membrane integrity (Basanez et al 2001;Duan et al 2010;Luan et al 2010;Zhang et al 2009). As shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Induction of apoptosis with mitochondrial membrane depolarization by a glycyrrhetinic acid derivative in human leukemia K562 cells

Gao

Kang

et al. 2012

Cytotechnology

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Glycyrrhetinic acid (GA) is the active compound in Glycyrrhizae radix, a famous traditional Chinese medicine. Recently the anticancer activity of GA became the focus of scientific interest and many GA derivatives were developed as anti-tumor lead compounds. We previously reported that AEGA, a GA derivative, has proliferation inhibition and apoptosis-inducing activity in various human tumor cells. The present study was undertaken to further investigate the molecular mechanisms involved in AEGA-induced apoptosis in human leukemia K562 cells. AEGA can inhibit the growth of K562 cells in dose- and time-dependent manners determined by the MTT assay. Induction of apoptosis was evidenced by morphological changes and biochemical markers such as cell shrinkage, chromatin condensation and DNA ladder formation. Further mechanistic analysis revealed that AEGA induced apoptosis through the collapse of mitochondrial membrane potential, the accumulation of the cytosolic cytochrome c and the activation of caspase-9 and caspase-3. The apoptosis induction by AEGA was associated with the alteration in the ratio of Bcl-2/Bax protein expression. These results suggest that AEGA may induce apoptosis through a mitochondria-mediated pathway, and might have the therapeutic value against hematological malignancies.

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Suppression of human lung cancer cell growth and migration by berbamine

Cited by 31 publications

References 19 publications

CaMKII γ, a critical regulator of CML stem/progenitor cells, is a target of the natural product berbamine

CaMKII γ, a critical regulator of CML stem/progenitor cells, is a target of the natural product berbamine

Perifosine induces cell cycle arrest and apoptosis in human hepatocellular carcinoma cell lines by blockade of Akt phosphorylation

Induction of apoptosis with mitochondrial membrane depolarization by a glycyrrhetinic acid derivative in human leukemia K562 cells

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