Breaking Advances Highlights from Recent Cancer Literature

Pancreatic cancers are inherently refractory to conventional chemotherapies. Gemcitabine [20,20-difluoro-20deoxycytidine (dFdC)] is currently used as a first-line treatment against locally advanced and metastatic adenocarcinoma of the pancreas. Gemcitabine is phosphorylated intracellularly to its active diphosphate (dFdC-DP) and triphosphate (dFdC-TP) forms that inhibit DNA and RNA replication. Membrane-bound nucleoside transporters are prerequisites for hydrophilic gemcitabine to enter cells because cells deficient in nucleoside transporter are resistant to gemcitabine cytotoxicity. Studies to date suggest 2 transporters from each of the human concentrative nucleoside transporter family (hCNT1 and hCNT3) and the equilibrative nucleoside transporter family (hENT1 and hENT2) are capable of translocating gemcitabine across the cell surface. Despite the expression of one or more of the aforementioned transporters in most cells types, hENT1 is generally considered to be predominantly involved in gemcitabine transport in tumors as its expression correlates with cellular proliferation. Clinical evidence also shows that pancreatic tumor cells with high hENT1 expression exhibit increased gemcitabine chemosensitivity. The present study establishes a role for the human concentrative nucleoside transporter-1 (hCNT1) in regulating the chemosensitivity of human pancreatic cancer cells to gemcitabine. Pharmacologic inhibition of hCNT1 degradation moderately increased cell surface hCNT1 expression and cellular gemcitabine transport in MIA PaCa-2 cells. Constitutive hCNT1 expression reduced clonogenic survival of MIA PaCa-2 cells and steeply augmented gemcitabine transport and chemosensitization. In addition to supporting a putative tumor suppressor role for hCNT1, the present findings highlight hCNT1 as a potential candidate to render drug-resistant pancreatic cancer cells amenable to chemotherapy. (Image from cited article courtesy of publisher.)