Berbamine derivatives: A novel class of compounds for anti-leukemia activity

Xie, Jinwen; Ma, Tongmei; Gu, Ying; Zhang, Xuzhao; Qiu, Xi; Zhang, Lei; Xu, Rongzhen; Yu, Yongping

doi:10.1016/j.ejmech.2009.02.018

Cited by 46 publications

(28 citation statements)

References 21 publications

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“…35,36 Our previous studies showed that the natural product berbamine analogs exhibit antiproliferative effects on IM-resistant CML cells, 17,18 but it is unknown whether these compounds affect LSCs and T315I mutant Bcr-Abl clones of CML. Therefore, we used 2 pairs of CML cell models: IM-resistant K562 cells containing CD34 ϩ cells and IM-resistant KCL-22M cells harboring T315I mutants of Bcr-Abl, to determine whether berbamine affected LSCs and T315I mutant Bcr-Abl clones.…”

Section: Berbamine Overrides Tki-resistance To Lscs and T315i Mutant-mentioning

confidence: 99%

“…To determine whether berbamine-mediated antileukemia activity is mainly caused by inhibition of CaMKII ␥ activity, we synthesized 54 berbamine analogs with IC 50 for inhibition of cell proliferation spanning 3 orders of magnitude 18 and performed structure-activity relationship (SAR) analysis. O-(ethoxycabonylmethyl)berbamine) (BBD5), an inactive analog, was used as a negative control.…”

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

confidence: 99%

“…16 We previously demonstrated that berbamine and its derivatives potently inhibited the growth of imatinib (IM)-resistant CML cells but not normal hematopoietic cells. 17,18 Extensive scrutiny of its molecular targets and mechanism of action in the past few decades has provided important insights. 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.…”

Section: Introductionmentioning

confidence: 99%

“…17,18 Extensive scrutiny of its molecular targets and mechanism of action in the past few decades has provided important insights. 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.…”

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

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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: Berbamine Overrides Tki-resistance To Lscs and T315i Mutant-mentioning

confidence: 99%

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

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Chen

Meng³

et al. 2012

Blood

Self Cite

106

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“…So, it is direly needed to explore new anticancer agents from plants which can effectively kill cancer cells without damaging normal body cells. (Saleem at al, 2014), Catharanthus roseus (Cragg and Newman, 2005;Okouneva et al, 2003;Simeons et al, 2008), Podophyllum peltatum and Podophyllum emodi (Shoeb et al, 2006), Taxus brevifolia Nutt, Taxus baccata (Kingston, 2007;Hait et al, 2007), Camptotheca acuminate (Zhang et al, 2004, Fuchs et al, 2006, Berberis amarensis (Xie et al, 2009;Xu et al, 2006), Hvdrastis canadensis L (Wang et al, 2011;Patil et al, 2010), Tabebuia avellanedae (Li et al, 2000;De Almeida, 2009), Betula alba (Fulda, 2008), Colchicum autumnale (Dubey et al, 2008), Curcuma longa (Sa et al, 2010;Goel et al, 2008), Wikstroemia indica Diogo et al, 2009), Psoralea corylifolia (Moon et al, 2006;Dixon and Ferreira, 2002), Ochrosia elliptica (Kuo et al, 2006), Amoora rohituka and Dysoxylum binectariferum (Mans et al, 2000), Euphorbia peplus L. (Hampson et al, 2005), Ipomoeca batatas L (Ancuceanu and Istudor, 2004), Salvia prionitis (Deng et al, 2011), Centaurea schischkinii (Shoeb et al, 2005) have been known to possess anticancer activity.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic effect of methanol extract of Conyza bonariensis on DMBA-induced skin carcinogenesis: An in vivo study

Saleem

Naseer

Hussain

et al. 2015

Bangladesh J Pharmacol

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In the present study, we examined the cytotoxic effect of Conyza bonariensis (methanolic extract). The skin carcinogenesis was induced in two stages, first, applying tumor initiator, 7-12-dimethyl benz(a)antheracene and thereafter applying croton oil, a tumor promotor in Swiss albino mice. The morphological alterations observed and measured during the induction of skin ulceration, included; cumulative number of papilloma, tumor yield and tumor burden. C. bonariensis extract (300 and 600 mg/kg/day) was applied locally on mice skin for 16 weeks. The higher dose (600 mg/kg/day) inhibited the tumor formation up to 40% and showed a significant decline in cumulative number of papilloma of continuous group. The results indicated that extract increased the reduced glutathione, superoxide dismutase and catalase, and decreased lipid peroxidation compared to carcinogen group. Histopathological changes showed papilomatosis and ulceration in carcinogen control group. HPLC analysis indicated the presence of flavonoid i.e. quercetin which may be responsible for the cytotoxic action of C. bonariensis methanol extract.

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ChemInform Abstract: Berbamine Derivatives: A Novel Class of Compounds for anti‐Leukemia Activity.

Xie

et al. 2009

ChemInform

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Berbamine derivatives: A novel class of compounds for anti-leukemia activity

Cited by 46 publications

References 21 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

Cytotoxic effect of methanol extract of <i>Conyza bonariensis</i> on DMBA-induced skin carcinogenesis: An <i>in vivo</i> study

ChemInform Abstract: Berbamine Derivatives: A Novel Class of Compounds for anti‐Leukemia Activity.

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