Statin treatment of pancreatic cancer cells in vitro enhanced chemo efficacy

 

Pancreatic ductal adenocaricoma (PDAC) is characterised by a dense desmoplastic stroma. It has become increasingly appreciated that in order to effectively treat pancreatic cancer both the tumour stroma and the cancer cells themselves must be targeted. The pancreatic cancer microenvironment has broad immunosuppressive and metastatic promoting properties mediated by many of the stroma resident cells including M2 polarised macrophages.

M2 macrophages secrete TGF-β1 which is known to mediate epithelial to mesenchymal transition (EMT) of pancreatic cancer cells yielding stem-like cell properties including enhanced resistance to the chemotherapeutic gemcitabine. A recent paper found that it was possible to inhibit TGF-β1 secretion by macrophages in vitro and that this restored sensitivity of pancreatic cancer cell lines to gemcitabine [1].

Primary tumour associated macrophages (TAMs) were generated from mononuclear cells obtained from the peripheral blood of volunteers by culturing differentiated macrophages with pancreatic cancer cell line conditioned cell culture media. It was found that TAM conditioned media contained significantly more TGF-β1 than conditioned media from normal macrophages.

Statins are a class of cholesterol lowering drugs that act by inhibiting the enzyme HMG-CoA reductase. Treatment of the TAMs with the statin Simvastatin reduced TGF-β1 secretion. Conditioned media from Simvastatin treated TAMs allowed greater killing of pancreatic cancer cell lines upon gemcitabine application than untreated TAM conditioned media. This was probably due to a decreased cancer cell EMT phenotype in the Simvastatin treatment arm. This study showed in vitro that statins have potential applications for pancreatic cancer therapy by reducing the ability of the microenvironment to produce chemotherapy resistant pancreatic cancer cells.

Refs

  1. Xian G, Zhao J, Qin C, Zhang Z, Lin Y, Su Z. Simvastatin attenuates macrophage-mediated gemcitabine resistance of pancreatic ductal adenocarcinoma by regulating the TGF-β1/Gfi-1 axis. Cancer Lett. 2016 Nov 10. Pii: S0304-3835(16)30684-X. doi: 10.1016/j.canlet.2016.11.006. PubMed PMID: 27840243.
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