A Novel Drug Induces Apoptosis in Breast Cancer Cells

Institution: Stanford University
Investigator(s): Glenn Rosen, M.D. -
Award Cycle: 1998 (Cycle IV) Grant #: 4JB-0057 Award: $228,595
Award Type: IDEAS II
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (1998)
Despite the development of new chemotherapeutic agents and aggressive treatment regimens, improvements in the long-term survival for breast cancer patients has been disappointing. This is often due to genetic mutations in the cancer cells that make them resistant to otherwise effective therapy. Also, there are inherent limitations in the drugs used to treat breast cancer. For example, some problems with chemotherapy include toxicity, the development of tumors that are resistant to chemotherapy, and the ability of chemotherapy to kill only rapidly dividing cells. A critical genetic defect in breast cancer is found in the p53 tumor suppressor gene, which makes p53 non-functional. Normally, p53 sensitizes the tumor cell to chemotherapy, which will induce programmed cell death (apoptosis). Our efforts are focused on new approaches to induce apoptosis in breast cancer cells, even if the cells lack functional p53 or are resistant to chemotherapy.

Tumor necrosis factor (TNF), which regulates inflammatory responses and combats tumor growth, can induce cell death in tumor cells regardless of their p53 status and resistance to chemotherapy. TNF family members, however, also activate pathways in breast cancer cells that protect the cell from the cytotoxic action of the TNF. Recently, we have observed that a compound called PG490 that contains triptolide, a chemical derived from a traditional Chinese herb will (i) induce apoptosis in breast cancer cells, (ii) enhance chemotherapy-induced cytotoxicity, and (iii) induce apoptosis in multidrug-resistant breast cancer cells. PG490 also sensitizes breast cancer cells to apoptosis by members of the TNF family by blocking an inhibitor of apoptosis. Our project aims to investigate novel approaches to kill tumor cells both with PG490 alone and in combination with members of the TNF family. Most critical, we will study how to enhance cytotoxicity for breast tumors that have mutations in the p53 gene and where drug resistance is present. PG490 and members of the TNF family, unlike chemotherapy, also kill slowly dividing or quiescent cells. Most cells within a tumor at any one time are not dividing or are dividing slowly, so our approach has the advantage of targeting cells that evade the effects of chemotherapy and other common therapies aimed at dividing cells.

These studies aim to provide a framework for future efforts that will examine the efficacy and safety of PG490 and members of the TNF family in animal breast cancer models. Our eventual goal is to pursue these studies in patients with breast cancer. As new technologies to detect breast cancer in younger women are developed, we must focus our attention on the therapeutic issues to ensure their long-term survival.


Final Report (2000)
Despite the development of new chemotherapeutic agents, improvement in survival of patients with advanced breast cancer has been disappointing. The goal of our studies is to identify novel methods to enhance the killing of breast cancer cells. Breast cancer cells can become less sensitive to chemotherapy through development of mutations in the p53 tumor suppressor gene and through overexpression of a multidrug resistant gene. Tumor necrosis factor (TNF), which regulates inflammatory response and combats tumor growth, can induce cell death in tumor cells regardless of their p53 status and resistance to chemotherapy. TNF family members, however, also activate pathways in breast cancer cells that protect the cells from the cytotoxic action of TNF. We found that a compound PG490, composed of purified triptolide, induces cell death in breast cancer cells, enhances chemotherapy-induced cytotoxicity and sensitizes breast cancer cells to TNF-induced cell death. Triptolide is a small molecule that is derived from a traditional Chinese herb. We have recently characterized the mechanism by which PG490 works with TNF in tumor cells. We found that PG490 suppressed the ability of TNF to turn on a cell death inhibitory pathway which is mediated by the NF-KB protein. We have also recently shown how PG490 enhances the ability of chemotherapy to kill tumor cells. We extended these studies to animal solid tumor models using PG490-88, a derivative of PG490, alone and in combination with chemotherapy. We found that PG490-88 alone induces tumor regression and acts in synergy with chemotherapy to induce regression of diverse solid tumors. We will continue to examine the mechanism of how PG490 kills tumor cells alone and in combination with TNF family members and chemotherapy. PG490 or a derivative of PG490 will hopefully become a novel effective treatment for patients with advanced breast cancer.

PG490 (Triplotide) cooperates with tumor necrosis factor-alpha to induce apoptosis in tumor cells
Periodical:Journal of Biological Chemistry
Index Medicus: J Biol Chem
Authors: Lee KY, Chang W-T, Qiu D, Kao PN, and Rosen GD
Yr: 1999 Vol: 274 Nbr: 19 Abs: Pg:13451-13455

Triptolide sensitizes lung cancer cells to TRAIL-induced apoptosis by inhibition of NF-kB
Periodical:American Journal of Respiratory and Critical Care Medicine
Index Medicus: Am J Respir Crit Care Med
Authors: Lee K-Y, Rosen GD
Yr: 1999 Vol: 159 Nbr: Abs: Pg:A208

Triptolide and chemotherapy cooperate in tumor cell apoptosis. A role for the p53 pathway
Periodical:Journal of Biological Chemistry
Index Medicus: J Biol Chem
Authors: Chang WT, Kang JJ, Lee KY, Wei K, Anderson E, Gotmare S, Ross JA, Rosen GD
Yr: 2000 Vol: 276 Nbr: 3 Abs: Pg:2221-7

Triptolide induces apoptosis in solid tumor cells and enhances chemotherapy-induced apoptosis: a role for the p53 pathway
Periodical:Cold Spring Harbor Symposium on Quantitative Biology
Index Medicus: Cold Spring Harb Symp Quant Biol
Authors: Kang JJ, Lee K-Y, Wei K, Anderson E, Gotmare S, and Rosen GD
Yr: 0 Vol: 103 Nbr: Abs: Pg: