CCR5 blockage by maraviroc induces cytotoxic and apoptotic effects in colorectal cancer cells

被引:41
作者
Pervaiz, Asim [1 ]
Ansari, Shariq [1 ]
Berger, Martin R. [1 ]
Adwan, Hassan [1 ]
机构
[1] German Canc Res Ctr, Toxicol & Chemotherapy Unit, D-69120 Heidelberg, Germany
关键词
C-C chemokine receptor type 5; Maraviroc; SW480; SW620; Caspases activation; Apoptosis induction; CHEMOKINE RECEPTOR CCR5; MOLECULAR-CLONING; EXPRESSION; SYSTEM; INHIBITION; ANTAGONIST; CASPASES; CYCLIN; BETA;
D O I
10.1007/s12032-015-0607-x
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Alterations in the expression of C-C chemokine receptor type 5 (CCR5 or CD195) have been correlated with disease progression in different cancers. Recently, a few investigations have reported the blockage of this receptor by an antagonist (maraviroc) and its antineoplastic effects on tumor cell growth. However, little is known about the mechanistic reasons behind these antineoplastic effects of CCR5 blockage by maraviroc. In this study, we blocked the CCR5 receptor by maraviroc in SW480 and SW620 colorectal cancer cells to study the resulting changes in biological properties and related pathways. This blockage induced significantly reduced proliferation and a profound arrest in G1 phase of the cell cycle. Concomitantly, maraviroc caused significant signs of apoptosis at morphological level. Significant modulation of multiple apoptosis-relevant genes was also noticed at mRNA levels. In addition, we found remarkable increases in cleaved caspases at protein level. These modulations led us to propose a signaling pathway for the observed apoptotic effects. In conclusion, blocking the CCR5 by maraviroc induces significant cytotoxic and apoptotic effects in colorectal cancer cells. Thus, maraviroc can be considered a model compound, which may foster the development of further CCR5 antagonists to be used for the treatment of colorectal cancer.
引用
收藏
页数:10
相关论文
共 45 条
[1]   Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects [J].
Abel, Samantha ;
Russell, Deborah ;
Whitlock, Lyndsey A. ;
Ridgway, Caroline E. ;
Nedderman, Angus N. R. ;
Walker, Donald K. .
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2008, 65 :60-67
[2]   Death without caspases, caspases without death [J].
Abraham, MC ;
Shaham, S .
TRENDS IN CELL BIOLOGY, 2004, 14 (04) :184-193
[3]   Chemokine: Receptor structure, interactions, and antagonism [J].
Allen, Samantha J. ;
Crown, Susan E. ;
Handel, Tracy M. .
ANNUAL REVIEW OF IMMUNOLOGY, 2007, 25 :787-820
[4]  
[Anonymous], 2020, CA Cancer J Clin, DOI DOI 10.3322/CAAC.21590
[5]   Cancer and the chemokine network [J].
Balkwill, F .
NATURE REVIEWS CANCER, 2004, 4 (07) :540-550
[6]   Inflammation and cancer: back to Virchow? [J].
Balkwill, F ;
Mantovani, A .
LANCET, 2001, 357 (9255) :539-545
[7]   CCL5 Neutralization Restricts Cancer Growth and Potentiates the Targeting of PDGFRβ in Colorectal Carcinoma [J].
Cambien, Beatrice ;
Richard-Fiardo, Peggy ;
Karimdjee, Babou F. ;
Martini, Violette ;
Ferrua, Bernard ;
Pitard, Bruno ;
Schmid-Antomarchi, Heidy ;
Schmid-Alliana, Annie .
PLOS ONE, 2011, 6 (12)
[8]   Tumor-Derived Chemokine CCL5 Enhances TGF-β-Mediated Killing of CD8+ T Cells in Colon Cancer by T-Regulatory Cells [J].
Chang, Li-Yuan ;
Lin, Yung-Chang ;
Mahalingam, Jayashri ;
Huang, Ching-Tai ;
Chen, Ten-Wen ;
Kang, Chiao-Wen ;
Peng, Hui-Min ;
Chu, Yu-Yi ;
Chiang, Jy-Ming ;
Dutta, Avijit ;
Day, Yuan-Ji ;
Chen, Tse-Ching ;
Yeh, Chau-Ting ;
Lin, Chun-Yen .
CANCER RESEARCH, 2012, 72 (05) :1092-1102
[9]   Initiator caspases in apoptosis signaling pathways [J].
Chen, M ;
Wang, J .
APOPTOSIS, 2002, 7 (04) :313-319
[10]   CC Chemokine Receptor 5: The Interface of Host Immunity and Cancer [J].
Coral de Oliveira, Carlos Eduardo ;
Maeda Oda, Julie Massayo ;
Guembarovski, Roberta Losi ;
de Oliveira, Karen Brajao ;
Ariza, Carolina Batista ;
Soni Neto, Jamil ;
Banin Hirata, Bruna Karina ;
Ehara Watanabe, Andmaria Angelica .
DISEASE MARKERS, 2014, 2014