RNAi Targeting CXCR4 Inhibits Tumor Growth Through Inducing Cell Cycle Arrest and Apoptosis

Yu, Tao; Wu, Yingying; Huang, Yi; Yan, Chaoran; Liu, Ying; Wang, Zongsheng; Wang, Xiaoyi; Wen, Yu-ming; Wang, Changmei; Li, Longjiang

doi:10.1038/mt.2011.257

Cited by 35 publications

(24 citation statements)

References 45 publications

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“…In this report, we showed that LY25109204 caused a significant and concentration-dependent decrease of nuclear intensity in the Namalwa xenograft model, suggesting that it may affect the G 1 to G 2 -M progression of the cell cycle. The cell cycle and proliferation effects observed in this model were consistent with other reports (3,12,30). Surprisingly, in the lymphoma Namalwa xenograft model, we have not observed significant impact on the tumor vasculature based on CD31 staining.…”

Section: Discussionsupporting

confidence: 81%

Identification of LY2510924, a Novel Cyclic Peptide CXCR4 Antagonist That Exhibits Antitumor Activities in Solid Tumor and Breast Cancer Metastatic Models

Peng

Zhang

Paul

et al. 2015

Molecular Cancer Therapeutics

127

129

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Emerging evidence demonstrates that stromal cell-derived factor 1 (SDF-1) and CXCR4, a chemokine and chemokine receptor pair, play important roles in tumorigenesis. In this report, we describe a small cyclic peptide, LY2510924, which is a potent and selective CXCR4 antagonist currently in phase II clinical studies for cancer. LY2510924 specifically blocked SDF-1 binding to CXCR4 with IC 50 value of 0.079 nmol/L, and inhibited SDF-1-induced GTP binding with Kb value of 0.38 nmol/L. In human lymphoma U937 cells expressing endogenous CXCR4, LY2510924 inhibited SDF-1-induced cell migration with IC 50 value of 0.26 nmol/L and inhibited SDF-1/ CXCR4-mediated intracellular signaling. LY2510924 exhibited a concentration-dependent inhibition of SDF-1-stimulated phospho-ERK and phospho-Akt in tumor cells. Biochemical and cellular analyses revealed that LY2510924 had no apparent agonist activity. Pharmacokinetic analyses suggested that LY2510924 had acceptable in vivo stability and a pharmacokinetic profile similar to a typical small-molecular inhibitor in preclinical species. LY2510924 showed dose-dependent inhibition of tumor growth in human xenograft models developed with non-Hodgkin lymphoma, renal cell carcinoma, lung, and colon cancer cells that express functional CXCR4. In MDA-MB-231, a breast cancer metastatic model, LY2510924 inhibited tumor metastasis by blocking migration/homing process of tumor cells to the lung and by inhibiting cell proliferation after tumor cell homing. Collectively, the preclinical data support further investigation of LY2510924 in clinical studies for cancer. Mol Cancer Ther; 14(2); 480-90. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 81%

Identification of LY2510924, a Novel Cyclic Peptide CXCR4 Antagonist That Exhibits Antitumor Activities in Solid Tumor and Breast Cancer Metastatic Models

Peng

Zhang

Paul

et al. 2015

Molecular Cancer Therapeutics

127

129

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“…To extend these observations to human T-ALL, we first silenced CXCR4 in human Jurkat T-ALL cells using two distinct shRNAs (Yu et al, 2012) (Figures 6A and 6B; Figure S4A) and analyzed their in vitro and in vivo phenotypes. We found that CXCR4 silencing inhibited Jurkat cell migration and proliferation while increasing apoptosis (Figures 6C-6E; Figures S4B-S4D).…”

Section: Cxcr4 Is Required For Human T-all Leukemogenicitymentioning

confidence: 98%

CXCR4 Is Required for Leukemia-Initiating Cell Activity in T Cell Acute Lymphoblastic Leukemia

et al. 2015

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Impaired cell migration has been demonstrated in T cell acute lymphoblastic leukemia (T-ALL) cells upon calcineurin inactivation, among other phenotypic traits including increased apoptosis, inhibition of cell proliferation, and ultimately inhibition of leukemia-initiating cell (LIC) activity. Herein we demonstrate that the chemokine receptor CXCR4 is essential to the LIC activity of T-ALL leukemic cells both in NOTCH-induced mouse T-ALL and human T-ALL xenograft models. We further demonstrate that calcineurin regulates CXCR4 cell-surface expression in a cortactin-dependent manner, a mechanism essential to the migratory properties of T-ALL cells. Because 20%-25% of pediatric and over 50% of adult patients with T-ALL do not achieve complete remission and relapse, our results call for clinical trials incorporating CXCR4 antagonists in T-ALL treatment.

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“…AMD3100 significantly inhibited the lung metastasis, ameliorated body weight loss, and improved the survival rate of mice. Blocking CXCR4 via an siRNA strategy can also induce anti-tumor effects [114, 115]. Furthermore, TN14003, a small synthetic peptide antagonist of CXCR4, can reduce tumor growth, microvessel density, and lung metastasis in tumor-bearing nude mice (Table 1 ) [116].…”

Section: Cxcr4 Inhibition Against Head and Neck Malignanciesmentioning

confidence: 99%

Targeting Chemokine Receptor CXCR4 for Treatment of HIV-1 Infection, Tumor Progression, and Metastasis

Choi¹,

Yang²,

Xu³

et al. 2014

CTMC

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The chemokine receptor CXCR4 is required for the entry of human immunodeficiency virus type 1 (HIV-1) into target cells and for the development and dissemination of various types of cancers, including gastrointestinal, cutaneous, head and neck, pulmonary, gynecological, genitourinary, neurological, and hematological malignancies. The T-cell (T)-tropic HIV-1 strains use CXCR4 as the entry coreceptor; consequently, multiple CXCR4 antagonistic inhibitors have been developed for the treatment of acquired immune deficiency syndrome (AIDS). However, other potential applications of CXCR4 antagonists have become apparent since its discovery in 1996. In fact, increasing evidence demonstrates that epithelial and hematopoietic tumor cells exploit the interaction between CXCR4 and its natural ligand, stromal cell-derived factor (SDF)-1α, which normally regulates leukocyte migration. The CXCR4 and/or SDF-1α expression patterns in tumor cells also determine the sites of metastatic spread. In addition, the activation of CXCR4 by SDF-1α promotes invasion and proliferation of tumor cells, enhances tumor-associated neoangiogenesis, and assists in the degradation of the extracellular matrix and basement membrane. As such, the evaluation of CXCR4 and/or SDF-1α expression levels has a significant prognostic value in various types of malignancies. Several therapeutic challenges remain to be overcome before the use of CXCR4 inhibitors can be translated into clinical practice, but promising preclinical data demonstrate that CXCR4 antagonists can mobilize tumor cells from their protective microenvironments, interfere with their metastatic and tumorigenic potentials, and/or make tumor cells more susceptible to chemotherapy.

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RNAi Targeting CXCR4 Inhibits Tumor Growth Through Inducing Cell Cycle Arrest and Apoptosis

Cited by 35 publications

References 45 publications

Identification of LY2510924, a Novel Cyclic Peptide CXCR4 Antagonist That Exhibits Antitumor Activities in Solid Tumor and Breast Cancer Metastatic Models

Identification of LY2510924, a Novel Cyclic Peptide CXCR4 Antagonist That Exhibits Antitumor Activities in Solid Tumor and Breast Cancer Metastatic Models

CXCR4 Is Required for Leukemia-Initiating Cell Activity in T Cell Acute Lymphoblastic Leukemia

Targeting Chemokine Receptor CXCR4 for Treatment of HIV-1 Infection, Tumor Progression, and Metastasis

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