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Gold (I) N-heterocyclic carbene complex inhibits mouse melanoma growth by p53 upregulation

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Title Gold (I) N-heterocyclic carbene complex inhibits mouse melanoma growth by p53 upregulation
 
Creator Nandy, Abhishek
Dey, Sumit Kumar
Das, Sujata
Mundal, Rudra Narayan
Dinda, Joydev
Das Saha, Krishna
 
Subject Cancer Biology and Inflammatory Disorder Division
 
Description Cancer treatment using gold (I) complexes is becoming popular. In this study, a gold (I) N-heterocyclic
complex designated as complex 3 was synthesized, its cytotoxicity was examined, and its anti-melanoma activity wasevaluated in vitro and in vivo. Viability of cancer cells was determined by MTT assay upon treatment with various concentrations of a gold (I) N-heterocyclic carbene complex (complex 3) in a dose and time dependent manner. Mouse melanoma cells B16F10 were selected for further apoptotic studies, including flowcytometric analysis of annexin binding, cell cycle arrest, intracellular ROS generation and loss in the mitochondrial membrane potential. ELISA based assays were done for
caspase activities and western blots for determining the expression of various survival and apoptotic proteins.
Immunocytology was performed to visualize the translocation of p53 to the nucleus. B16F10 cells were inoculated
into mice and post tumor formation, complex 3 was administered. Immunohistology was performed to determine the
expressions of p53, p21, NF-κB (p65 and p50), MMP-9 and VEGF. Student’s t test was used for determining statistical
significance. The survival rate data were analyzed by Kaplan-Meier plots.Complex 3 markedly inhibited the growth of HCT 116, HepG2, and A549, and induced apoptosis in B16F10
cells with nuclear condensation, DNA fragmentation, externalization of phosphatidylserine, activation of caspase 3 and caspase 9, PARP cleavage, downregulation of Bcl-2, upregulation of Bax, cytosolic cytochrome c elevation, ROS generation, and mitochondrial membrane potential loss indicating the involvement of an intrinsic mitochondrial death pathway. Further, upregulation of p53, p-p53 (ser 15) and p21 indicated the role of p53 in complex 3 mediated apoptosis. The complex reduced tumor size, and caused upregulation of p53 and p21 along with downregulation of NF-κB (p65 and p50), VEGF and MMP-9. These results suggest that it induced anti-melanoma effect in vitro and in vivo by modulating p53 and other apoptotic factors. The gold (I) N-heterocyclic carbene complex (C22H26N6AuO2PF6) designated as complex 3 induced
ROS and p53 dependent apoptosis in B16F10 cells involving the mitochondrial death pathway along with suppression of melanoma tumor growth by regulating the levels of pro and anti apoptotic factors (p53, p21, NF-κB, VEGF and MMP-9).
 
Publisher BioMed Central
 
Date 2014
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/2048/1/MOLECULAR_CANCER__Volume_13_____Article_Number_57;2014[45].pdf
Nandy, Abhishek and Dey, Sumit Kumar and Das, Sujata and Mundal, Rudra Narayan and Dinda, Joydev and Das Saha, Krishna (2014) Gold (I) N-heterocyclic carbene complex inhibits mouse melanoma growth by p53 upregulation. Molecular Cancer, 13 (57).
 
Relation http://www.eprints.iicb.res.in/2048/