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Published on: October 4, 2022
Smac mimetic-derived augmentation of chemotherapeutic response in experimental pancreatic cancer
Niranjan Awasthi1, Amanda Kirane, Margaret A Schwarz
1Division of Surgical Oncology, Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Background:
Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to conventional chemotherapy, in part due to the overexpression of inhibitors of apoptosis proteins (IAPs). Smac is an endogenous IAP-antagonist, which renders synthetic Smac mimetics attractive anticancer agents. We evaluated the benefits of combining a Smac mimetic, JP1201 (JP), with conventional chemotherapy agents used for PDAC management.
Methods:
Cell viability assays and protein expression analysis were performed using WST-1 reagent and Western blotting, respectively. Apoptosis was detected by annexin V/propidium iodide staining. In vivo tumor growth and survival studies were performed in murine PDAC xenografts.
Results:
JP and gemcitabine (Gem) inhibited PDAC cell proliferation with additive effects in combination. The percentage of early apoptotic cells in controls, JP, Gem and JP + Gem was 17%, 26%, 26% and 38%, respectively. JP-induced apoptosis was accompanied by PARP-1 cleavage. Similar additive anti-proliferative effects were seen for combinations of JP with doxorubicin (Dox) and docetaxel (DT). The JP + Gem combination caused a 30% decrease in tumor size in vivo compared to controls. Median animal survival was improved significantly in mice treated with JP + Gem (38 d) compared to controls (22 d), JP (28 d) or Gem (32 d) (p = 0.01). Animal survival was also improved with JP + DT treatment (32 d) compared to controls (16 d), JP (21 d) or DT alone (27 d).
Conclusions:
These results warrant further exploration of strategies that promote chemotherapy-induced apoptosis of tumors and highlight the potential of Smac mimetics in clinical PDAC therapy.
Insights
Combining Smac mimetic JP1201 with chemotherapy enhances apoptosis and survival in pancreatic cancer models. This approach shows promise for treating pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits resistance to conventional chemotherapy, partly due to elevated levels of inhibitors of apoptosis proteins (IAPs).
- Smac (second mitochondria-derived activator of caspases) is a natural antagonist of IAPs, making Smac mimetics potential anticancer agents.
- Synthetic Smac mimetics, like JP1201 (JP), are being investigated to overcome chemotherapy resistance in PDAC.
Purpose of the Study:
- To evaluate the efficacy of combining the Smac mimetic JP1201 with standard chemotherapy agents for PDAC treatment.
- To assess the impact of this combination therapy on cancer cell proliferation, apoptosis, and tumor growth in preclinical models.
Main Methods:
- Cell viability was assessed using WST-1 assays.
- Protein expression, including cleaved PARP-1, was analyzed by Western blotting.
- Apoptosis was quantified using annexin V/propidium iodide staining.
- In vivo studies involved murine PDAC xenografts to evaluate tumor growth and animal survival.
Main Results:
- JP1201 and gemcitabine (Gem) demonstrated additive anti-proliferative effects on PDAC cells, increasing apoptosis from 26% to 38%.
- JP1201 also showed additive effects with doxorubicin and docetaxel, inducing apoptosis and PARP-1 cleavage.
- In vivo, the JP1201 + Gem combination reduced tumor size by 30% and significantly improved median survival (38 days vs. 22 days for controls).
- JP1201 + docetaxel also improved survival compared to controls or single-agent treatment.
Conclusions:
- Combining Smac mimetics with chemotherapy agents can enhance chemotherapy-induced apoptosis in PDAC.
- These findings support the potential of Smac mimetics as a therapeutic strategy for pancreatic ductal adenocarcinoma.
- Further clinical investigation of Smac mimetics in PDAC treatment is warranted.
