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Review
. 2019 Sep 11;20(18):4504.
doi: 10.3390/ijms20184504.

Chemoresistance in Pancreatic Cancer

Siyuan Zeng  1 , Marina Pöttler  2 , Bin Lan  3 , Robert Grützmann  4 , Christian Pilarsky  5 , Hai Yang  6
Affiliations
Review

Chemoresistance in Pancreatic Cancer

Siyuan Zeng et al. Int J Mol Sci. .

Abstract

Pancreatic ductal adenocarcinoma (PDAC), generally known as pancreatic cancer (PC), ranks the fourth leading cause of cancer-related deaths in the western world. While the incidence of pancreatic cancer is displaying a rising tendency every year, the mortality rate has not decreased significantly because of late diagnosis, early metastasis, and limited reaction to chemotherapy or radiotherapy. Adjuvant chemotherapy after surgical resection is typically the preferred option to treat early pancreatic cancer. Although 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel can profoundly improve the prognosis of advanced pancreatic cancer, the development of chemoresistance still leads to poor clinical outcomes. Chemoresistance is multifactorial as a result of the interaction among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment. Nevertheless, more pancreatic cancer patients will benefit from precision treatment and targeted drugs. Therefore, we outline new perspectives for enhancing the efficacy of gemcitabine after reviewing the related factors of gemcitabine metabolism, mechanism of action, and chemoresistance.

Keywords: FOLFIRINOX; PDAC; chemoresistance; gemcitabine; pancreatic cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Gemcitabine molecular formula and structure.
Figure 2
Figure 2
Mechanism of action of gemcitabine. Gemcitabine activation and transport are governed by various enzymes. Nucleoside transporters include the human concentrative nucleoside transporters (hCNTs) and human equilibrative nucleoside transporters (hENTs). After gemcitabine enters the cell membrane, deoxycytidine kinase (dCK) is the first phosphorylated rate-limiting enzyme and phosphorylates gemcitabine to gemcitabine monophosphate (dFdCMP). Subsequently, complex intracellular converts to nucleotide gemcitabine diphosphate (dFdCDP) and triphosphate (dFdCTP). Gemcitabine metabolite dFdCTP inhibits ribonucleoside reductase (RR), an enzyme that regulates DNA biosynthesis, by controlling the formation of nucleoside triphosphates (NTPs). RR transforms CDP into dCDP, and its inhibitory effect leads to the decreased concentration of competitive dCTP pool cells required for DNA synthesis, thus promoting the binding of dFdCTP to DNA.
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References

    1. Rahib L., Smith B.D., Aizenberg R., Rosenzweig A.B., Fleshman J.M., Matrisian L.M. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–2921. doi: 10.1158/0008-5472.CAN-14-0155. - DOI - PubMed
    1. Kamisawa T., Wood L.D., Itoi T., Takaori K. Pancreatic cancer. Lancet. 2016;388:73–85. doi: 10.1016/S0140-6736(16)00141-0. - DOI - PubMed
    1. Rawla P., Sunkara T., Gaduputi V. Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors. World J. Oncol. 2019;10:10–27. doi: 10.14740/wjon1166. - DOI - PMC - PubMed
    1. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2018. CA A Cancer J. Clin. 2018;68:7–30. doi: 10.3322/caac.21442. - DOI - PubMed
    1. Kleeff J., Korc M., Apte M., La Vecchia C., Johnson C.D., Biankin A.V., Neale R.E., Tempero M., Tuveson D.A., Hruban R.H., et al. Pancreatic cancer. Nat. Rev. Dis. Primers. 2016;2:16022. doi: 10.1038/nrdp.2016.22. - DOI - PubMed