Induction of apoptosis of human B-CLL and ALL cells by a novel retinoid and its nonretinoidal analog

Zhang, Yuxiang; Dawson, Marcia I.; Mohammad, Ramzi M.; Rishi, Arun K.; Farhana, Lulu; Feng, Kai; Leid, Mark; Peterson, Valerie J.; Zhang, Xiao Kun; Edelstein, M; Eilander, David; Biggar, Sandra; Wall, Nathan R.; Reichert, Uwe; Fontana, Joseph A.

doi:10.1182/blood.v100.8.2917

Cited by 60 publications

(98 citation statements)

References 57 publications

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“…However, recent studies support that CD437 does not induce apoptosis through activation of RARg. 26 Such conclusion is also consistent with our recent finding that a novel related agent ST1926 is a potent inducer of apoptosis in spite of an almost complete loss of ability to transactivate RARs. 9 A novel observation of our previous study was the evidence that ST1926 is able to cause DNA strand breaks after a short-term exposure (6 h).…”

Section: Discussionsupporting

confidence: 91%

“…1,[21][22][23] Multiple and sometimes conflicting results have been reported concerning the molecular events mediating induction of apoptosis by synthetic retinoids. 1,3,[24][25][26] Some of these agents retain a weak ability to transactivate RARg. However, recent studies support that CD437 does not induce apoptosis through activation of RARg.…”

Section: Discussionmentioning

confidence: 99%

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Induction of apoptosis and stress response in ovarian carcinoma cell lines treated with ST1926, an atypical retinoid

et al. 2003

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To understand the molecular mechanisms mediating apoptosis induction by a novel atypical retinoid, ST1926, the cellular response to drug treatment was investigated in IGROV-1 ovarian carcinoma cells carrying wild-type p53 and a cisplatin-resistant p53 mutant subline (IGROV-1/Pt1). Despite a similar extent of drug-induced DNA strand breaks, the level of apoptosis was substantially higher in p53 wild-type cells. p53 activation and early upregulation of p53-target genes were consistent with p53-dependent apoptosis in IGROV-1 cells. Stress-activated protein kinases were activated in both cell lines in response to ST1926. This event and activation of AP-1 were more pronounced in IGROV-1/Pt1 cells, in which the modulation of DNA repair-associated genes suggests an increased ability to repair DNA damage. Inhibition of JNK or p38 stimulated ST1926-induced apoptosis only in IGROV-1 cells, whereas inhibition of ERKs enhanced apoptosis in both the cell lines. Such a pattern of cellular response and modulation of genes implicated in DNA damage response supports that the genotoxic stress is a critical event mediating drug-induced apoptosis. The results are consistent with apoptosis induction through p53-dependent andindependent pathways, regulated by MAP kinases, which likely play a protective role.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Induction of apoptosis and stress response in ovarian carcinoma cell lines treated with ST1926, an atypical retinoid

et al. 2003

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“…The elimination of antiapoptotic proteins will prevent the blockage of apoptosis. An example of this is active caspase-3, which cleaves Bcl-2 and Bcl-X (L) thereby eliminating these prosurvival proteins (Bossy-Wetzel and Green, 1999;Zhang et al, 2002). On the other hand, caspase-8 will cleave the pro-apoptotic protein BID.…”

Section: Caspasesmentioning

confidence: 99%

Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines

Holmes¹,

Soprano²,

Soprano³

2004

Journal Cellular Physiology

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Apoptosis is also known as programmed cell death. Apoptosis plays an essential role in maintaining normal tissue and cell physiology in multicellular organisms. Clearance of aberrant or pre-cancerous cells occurs through the induction of apoptosis. It has been reported that many tumors and tumor cell lines have dysfunctional apoptosis signaling, causing these tumors to escape immune monitoring and internal cellular control mechanisms. One potential cause of this dysfunctional apoptosis is the tumor suppressor p53, an important regulator of growth arrest and apoptosis that is mutated in over 50% of all cancers. Retinoids have great potential in the areas of cancer therapy and chemoprevention. While some tumor cells are sensitive to the growth inhibitory effects of natural retinoids such as all-trans-retinoic acid (ATRA), many ovarian tumor cells are not. 6-[3-(1-Admantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and fenretinide N-[4-hydroxyphenyl] retinamide (4-HPR) are conformationally restricted synthetic retinoids that induce growth arrest and apoptosis in both ATRA-sensitive and ATRA-resistant ovarian tumor cell lines. Recently, we have identified the molecular pathways of apoptosis induced by treatment of ovarian carcinoma cells with mutated p53 by CD437 and 4-HPR.

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“…The 3-Cl-AHPC was synthesized as we recently described. 27 Cell growth IL-3-transfected M07e cells as well as the KG-1 and HL-60R cells have been previously described. [28][29][30][31] The cells were grown in RPMI supplemented with 5% heat-inactivated fetal bovine serum (FBS) and 25 g/mL gentamicin in a 95% O 2 , 5% CO 2 , and 100% humidity environment.…”

Section: Methodsmentioning

confidence: 99%

“…20,21,26 In the present study, we assessed the ability of the AHPN analog 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) to induce apoptosis in a number of human AML cell lines as well as in primary cultures of leukemic blasts obtained from patients. The 3-Cl-AHPC differs from AHPN in its inability to recruit RAR coactivators and transactivate the RARs (Zhang et al 27 and data not shown). We found that 3-Cl-AHPC is a potent inducer of apoptosis in these cells, which display resistance to the antiproliferative/differentiating effects of tRA.…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog

Zhang

Dawson²,

Ning³

et al. 2003

Blood

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IntroductionAcute myelogenous leukemia (AML) is a heterogeneous disease composed of numerous subclassifications displaying a wide spectrum of phenotypes. 1,2 The major therapeutic approach to this disease has been the use of chemotherapeutic agents with associated life-threatening toxicity. Although nonspecific in their effects, these regimens have significantly increased the survival of AML patients. [3][4][5] Recently, more targeted therapy has been developed. Treatment of acute promyelocytic leukemia (APL) patients with trans-retinoic acid (tRA) results in the differentiation of the leukemic cells, with 90% of the patients achieving a complete remission. [6][7][8] The tRA exerts its effect by modulating gene expression through its role as a ligand to the retinoic acid nuclear receptors, RARs, with the subsequent binding of this complex to the retinoic acid response element (RARE) consensus sequences located in the regulatory regions of retinoid-responsive genes. 9 The selective sensitivity of APL cells to tRA-mediated differentiation resides in their specific expression of a unique promyelocytic leukemia (PML)-RAR␣ fusion product that results in the subsequent maturation arrest of these cells at the promyelocyte stage [10][11][12] ; exposure of these cells to a micromolar concentration of tRA allows for the degradation of the PML-RAR␣ fusion product, with subsequent maturation of the APL cells. [13][14] Unfortunately, the other AML subtypes as classified by the French-American-British (FAB) classification demonstrate inherent resistance to tRA-mediated differentiation and induction of apoptosis. 15,16 We and others have recently described a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN/CD437), which is a potent inducer of apoptosis in a variety of cell types and which displays resistance to tRA-mediated differentiation and apoptosis. [17][18][19][20][21] The mechanistic pathways by which AHPN induces apoptosis in malignant cells are not clearly defined. AHPN binds and transactivates both the RAR␤ and RAR␥ receptors. 22,23 The roles of these retinoid nuclear receptors in AHPN-mediated apoptosis are controversial. While some studies have suggested that binding and transactivation of RAR␥ are essential for AHPN/CD437-mediated apoptosis, 24,25 others have indicated that neither the RARs nor the retinoid X receptors (RXRs) to which AHPN does not bind or transactivate are involved. 20,21,26 bloodjournal.org FromIn the present study, we assessed the ability of the AHPN analog 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) to induce apoptosis in a number of human AML cell lines as well as in primary cultures of leukemic blasts obtained from patients. The 3-Cl-AHPC differs from AHPN in its inability to recruit RAR coactivators and transactivate the RARs (Zhang et al 27 and data not shown). We found that 3-Cl-AHPC is a potent inducer of apoptosis in these cells, which display resistance to the antiproliferative/differentiating effects of tRA. The 3-C...

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Induction of apoptosis of human B-CLL and ALL cells by a novel retinoid and its nonretinoidal analog

Cited by 60 publications

References 57 publications

Induction of apoptosis and stress response in ovarian carcinoma cell lines treated with ST1926, an atypical retinoid

Induction of apoptosis and stress response in ovarian carcinoma cell lines treated with ST1926, an atypical retinoid

Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines

Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog

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