Pancreatic cancer is resistant to conventional as well as novel anti-cancer therapies including TRAIL (Tumor Necrosis Factor-Related Apoptosis Inducing Ligand). Studies in our laboratories show that triptolide, a compound isolated from the Chinese plant Tripterygium wilfordii, sensitizes pancreatic cancer cells to cell death caused by TRAIL. These novel findings suggest that the combination of TRAIL and triptolide can emerge as an effective therapeutic strategy for pancreatic cancer. Our preliminary studies also provide some mechanistic insights and suggest that triptolide sensitizes pancreatic cancer cells to TRAIL induced cell death by two different mechanisms: 1) by sensitization of the lysosomes to TRAIL induced permeabilization;and 2) by abrogating TRAIL induced NF?B activation, thus counteracting pro-survival pathways induced by TRAIL.
In Aim 1 of the current grant proposal, the efficacy of combination therapy will be evaluated in three unique but complementary animal models of pancreatic cancer.
Aims 2 and 3 are designed to provide insights into the mechanism by which triptolide sensitizes pancreatic cancer cells to TRAIL induced cell death.
In Aim 2 we will evaluate the novel hypothesis that triptolide downregulates Mcl-1, Bcl-2 and Bcl-xl (anti- apoptotic members of Bcl-2 family which sequester Bax/Bak). Release of Bax and Bak, which are then activated by TRAIL, allows them to translocate to lysosomes and induce lysosomal membrane permeabilization).
In Aim 3 we will evaluate the novel hypothesis that triptolide downregulates TRIAL induced NF?B activation by inhibiting cIAP expression. Once unraveled, the mechanisms by which triptolide sensitizes pancreatic cancer cells to TRAIL will lead to the development of novel drug targets. Successful completion of these mechanistic and translational studies will eventually help in planning strategies to combine triptolide with TRAIL so that this combination can be used for the treatment of pancreatic cancer.

Public Health Relevance

Pancreatic cancer is resistant to conventional as well as novel anti-cancer therapies including TRAIL (Tumor Necrosis Factor-Related Apoptosis Inducing Ligand). Studies in our laboratories show that triptolide, a compound isolated from the Chinese plant Tripterygium wilfordii, sensitizes pancreatic cancer cells to cell death caused by TRAIL. In the current grant proposal, we intend to confirm the efficacy of the combination of TRAIL and triptolide against pancreatic cancer in animal models of pancreatic cancer, and investigate the mechanism of action of this combined therapy. Once unraveled, the mechanisms by which triptolide sensitizes pancreatic cancer cells to TRAIL will lead to the development of novel drug targets. Successful completion of these mechanistic and translational studies will eventually help in planning strategies to combine triptolide with TRAIL so that this combination can be used for the treatment of pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA170946-02
Application #
8507185
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (03))
Program Officer
Fu, Yali
Project Start
2012-07-06
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$452,316
Indirect Cost
$154,740
Name
University of Minnesota Twin Cities
Department
Surgery
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Banerjee, Sulagna; Nomura, Alice; Sangwan, Veena et al. (2014) CD133+ tumor initiating cells in a syngenic murine model of pancreatic cancer respond to Minnelide. Clin Cancer Res 20:2388-99
Chen, Zhiyu; Sangwan, Veena; Banerjee, Sulagna et al. (2014) Triptolide sensitizes pancreatic cancer cells to TRAIL-induced activation of the death receptor pathway. Cancer Lett 348:156-66
Mujumdar, Nameeta; Banerjee, Sulagna; Chen, Zhiyu et al. (2014) Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells. Am J Physiol Gastrointest Liver Physiol 306:G1011-20
MacKenzie, Tiffany N; Mujumdar, Nameeta; Banerjee, Sulagna et al. (2013) Triptolide induces the expression of miR-142-3p: a negative regulator of heat shock protein 70 and pancreatic cancer cell proliferation. Mol Cancer Ther 12:1266-75
Rousalova, Ilona; Banerjee, Sulagna; Sangwan, Veena et al. (2013) Minnelide: a novel therapeutic that promotes apoptosis in non-small cell lung carcinoma in vivo. PLoS One 8:e77411