Can We Increase the Sensitivity of Pancreatic Cancer Cells to Chemotherapeutics?

Researchers have identified small molecules that increase the ability of chemotherapeutic agents to kill pancreatic cancer cells and slow tumor growth in mice, according to the February issue of Gastroenterology.

One way that chemotherapeutics such gemcitabine, 5-fluorouracil, and platinum-based compounds kill cancer cells is by causing tumor suppressor proteins to accumulate in the nuclei and activate cell death. However, cancer cells respond by increasing production of proteins such as exportin-1 (more commonly called chromosome region maintenance-1 or CRM-1), which transport these proteins back out of their nuclei. This makes them resistant to chemotherapy.

Increased expression of CRM-1 has been correlated with shorter overall survival times of patients with different cancers, including pancreatic cancer.

Asfar S. Azmi et al. used a high-throughput, in silico, structure-based design to identify small, highly selective inhibitors of nuclear export (SINEs), which bind covalently to CRM-1 and irreversibly inhibit its export function.

They showed that oral administration of SINEs to mice significantly slowed growth of subcutaneous and orthotopic pancreatic tumors, compared with gemcitabine. No significant toxicities were observed, and the mice did not lose significant amounts of body weight.

The SINEs also inhibited proliferation and promoted apoptosis of cultured pancreatic cancer cells, but did not affect human pancreatic ductal epithelial cells.

Nuclei of cells incubated with the SINEs accumulated tumor-suppressor proteins (such as p27, FOXO, p73, and prostate apoptosis response-4 [PAR-4]). Azmi et al. showed that the SINEs inhibited interactions between CRM-1 and these proteins. Mutations in the region of CRM-1 that bind to SINEs (Cys-528) prevented their ability to block proliferation and induce apoptosis of pancreatic cancer cells.

Analysis of tumor remnants from mice showed that the SINEs disrupted the interaction between CRM-1 and PAR-4, activated PAR-4 signaling, and reduced proliferation of cancer cells (see below figure).

In cancer cells, increased levels of protein kinase A (PKA) lead to Par-4 phosphorylation (p-Par-4) and nuclear localization. However, the increased levels of CRM-1 then pump Par-4 out of the nucleus. SINEs such as KPTs inhibit CRM-1, leading to nuclear retention of p-Par-4 and apoptosis. In normal cells, levels of PKA and Par-4 are too low for KPTs to induce cell death.

In cancer cells, increased levels of protein kinase A (PKA) lead to Par-4 phosphorylation (p-Par-4), activation, and nuclear localization. However, the increased levels of CRM-1 then export Par-4 out of the nucleus. SINEs such as KPTs inhibit CRM-1, leading to nuclear retention of p-Par-4 and apoptosis. In normal cells, levels of PKA and Par-4 are too low for KPTs to induce cell death.

SINEs have broad specificity against different types of cancer cells, with median inhibitory concentrations (IC50s) in the submicromolar range, so they do not affect normal cells. They have recently entered phase I clinical trials for solid tumors (NCT01607905) and advanced hematologic malignancies (NCT01607892), but not yet for pancreatic cancer.

There have been previous approaches to block CRM-1−mediated nuclear export, such as with the CRM-1 inhibitor leptomycin B, but this reagent produced toxic side effects in a phase I trial. The small molecules of CRM-1 developed by Azmi et al. have higher levels of specificity, cancer cell selectivity, and lower toxicity, and might therefore be more effective and less toxic to patients.

Read the article online.
Azmi AS, Aboukameel A, Bao B, et al. Selective inhibitors of nuclear export block pancreatic cancer cell proliferation and reduce tumor growth in mice. Gastroenterology 2013;144:447–456.

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About Kristine Novak, PhD, Science Editor

Dr. Kristine Novak is the science editor for Gastroenterology and Clinical Gastroenterology and Hepatology, both published by the American Gastroenterological Association. She has worked as an editor at biomedical research journals and as a science writer for more than 12 years, covering advances in gastroenterology, hepatology, cancer, immunology, biotechnology, molecular genetics, and clinical trials. She has a PhD in cell biology and an interest in all areas of medical research.
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