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Am J Transl Res 2011;3(4):374-382
Original Article
Network modeling of CDF treated pancreatic cancer cells reveals a
novel c-myc-p73 dependent apoptotic mechanism
Asfar S. Azmi, Shadan Ali, Sanjeev Banerjee, Bin Bao, Mai’n Maitah, Philip A. Philip, Ramzi M. Mohammad, Fazlul
H. Sarkar
Department of Pathology and Oncology, Karmanos Cancer Institute, Wayne State University, Detroit MI, USA
Received June 29, 2011; Accepted July 17, 2011; Epub July 26, 2011; Published August 15, 2011
Abstract: Systems biology and molecular network modeling are important tools that are finding application in anti-
cancer drug discovery. These technologies can be utilized to map and evaluate the entire set of pathways
modulated by drugs in cancer cells without loosing key details. Such integrated approaches are especially useful
in understanding the mechanism of action of agents that do not have a defined target. Our novel compound CDF
(a synthetic analogue of curcumin), is one such multi-targeted agent with proven anti-cancer activity in vitro and in
vivo. However, its mechanism of action is not fully understood, and thus a thorough analysis of key pathways
targeted by CDF would be important for developing targeted and tailored therapy in the future. Applying Ingenuity
Pathway Analysis (IPA), we have mapped the pathways altered by CDF treatment of BxPC-3 pancreatic cancer
(PC) cells. Illumina HT-12 microarrays were performed on RNA extracted from CDF treated cells. IPA analysis of
gene expression at early time point (24 hrs) revealed deregulation of genes in the c-Myc hub. Western blot
analysis validated the activation of c-Myc, p73 and its downstream pro-apoptotic effector Bax with simultaneous
down-regulation of Bcl-2 in two distinct pancreatic cancer cell lines (BxPC-3 and Colo-357). In order to further
delineate the role of c-Myc in inducing apoptosis, siRNA silencing technology was used. As expected, c-Myc
siRNA knockdown resulted in abrogation of the growth inhibitory and apoptotic potential of CDF. In conclusion,
our results demonstrate a novel c-Myc driven apoptotic network activated by CDF in PC cells that is independent
of wild-type p53, and thus warrants further investigation on the clinical utility of CDF. (AJTR1106005).
Keywords: Systems biology, network modeling, curcumin, CDF, c-Myc, p73, p53, Bax, Bcl-2, apoptosis,
pancreatic cancer
Full Text PDF
Address all correspondence to:
Fazlul H. Sarkar, PhD
Department of Pathology
Wayne State University
Karmanos Cancer Institute
4100 John R,
740 HWCRC Building
Detroit MI-48201, USA
Tel: 313 576 8325
Fax: 313 576 8389
Email: fsarkar@med.wayne.edu
Original Article
Network modeling of CDF treated pancreatic cancer cells reveals a
novel c-myc-p73 dependent apoptotic mechanism
Asfar S. Azmi, Shadan Ali, Sanjeev Banerjee, Bin Bao, Mai’n Maitah, Philip A. Philip, Ramzi M. Mohammad, Fazlul
H. Sarkar
Department of Pathology and Oncology, Karmanos Cancer Institute, Wayne State University, Detroit MI, USA
Received June 29, 2011; Accepted July 17, 2011; Epub July 26, 2011; Published August 15, 2011
Abstract: Systems biology and molecular network modeling are important tools that are finding application in anti-
cancer drug discovery. These technologies can be utilized to map and evaluate the entire set of pathways
modulated by drugs in cancer cells without loosing key details. Such integrated approaches are especially useful
in understanding the mechanism of action of agents that do not have a defined target. Our novel compound CDF
(a synthetic analogue of curcumin), is one such multi-targeted agent with proven anti-cancer activity in vitro and in
vivo. However, its mechanism of action is not fully understood, and thus a thorough analysis of key pathways
targeted by CDF would be important for developing targeted and tailored therapy in the future. Applying Ingenuity
Pathway Analysis (IPA), we have mapped the pathways altered by CDF treatment of BxPC-3 pancreatic cancer
(PC) cells. Illumina HT-12 microarrays were performed on RNA extracted from CDF treated cells. IPA analysis of
gene expression at early time point (24 hrs) revealed deregulation of genes in the c-Myc hub. Western blot
analysis validated the activation of c-Myc, p73 and its downstream pro-apoptotic effector Bax with simultaneous
down-regulation of Bcl-2 in two distinct pancreatic cancer cell lines (BxPC-3 and Colo-357). In order to further
delineate the role of c-Myc in inducing apoptosis, siRNA silencing technology was used. As expected, c-Myc
siRNA knockdown resulted in abrogation of the growth inhibitory and apoptotic potential of CDF. In conclusion,
our results demonstrate a novel c-Myc driven apoptotic network activated by CDF in PC cells that is independent
of wild-type p53, and thus warrants further investigation on the clinical utility of CDF. (AJTR1106005).
Keywords: Systems biology, network modeling, curcumin, CDF, c-Myc, p73, p53, Bax, Bcl-2, apoptosis,
pancreatic cancer
Full Text PDF
Address all correspondence to:
Fazlul H. Sarkar, PhD
Department of Pathology
Wayne State University
Karmanos Cancer Institute
4100 John R,
740 HWCRC Building
Detroit MI-48201, USA
Tel: 313 576 8325
Fax: 313 576 8389
Email: fsarkar@med.wayne.edu
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