• JOSE PRADOS

      Articles written in Journal of Biosciences

    • MMR-proficient and MMR-deficient colorectal cancer cells: 5-Fluorouracil treatment response and correlation to CD133 and MGMT expression

      JAIME A OLIVER RAU´L ORTIZ CRISTINA JIME´NEZ-LUNA LAURA CABEZA GLORIA PERAZZOLI OCTAVIO CABA CRISTINA MESAS CONSOLACIO´N MELGUIZO JOSE PRADOS

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      Cancer stem cells (CSCs) from colorectal cancer (CRC), characterized by CD133 expression, have beenassociated with 5-fluorouracile (5-FU) chemoresistance. DNA repair mechanisms, such as O6-alkylguanineDNA alkyltransferase (MGMT) and mismatch repair (MMR) systems, have also been correlated to 5-FUresistance in CRC. The aim of this study was to evaluate the modulation of CD133 and MGMT in MMRproficientand MMR-deficient CRC cells under 5-FU treatment and the effect of this drug in CSCs. CD133 andMGMT methylation status were determined in MMR-proficient (SW480 and HT29) and MMR-deficient (RKOand HCT116) cell lines by methylation-specific PCRs. SW480 and RKO were selected to determine modulationof CD133, MGMT and MMR expression after 5-FU treatment by qPCR. In addition, CD133, MGMTand MMR were analyze in SW480 and RKO CSCs. No association between promoter methylation and MGMTand CD133 expression was found. 5-FU treatment increased CD133 expression independently to MMR statusin SW480 and RKO and was able to increase hMLH1 expression in RKO, a MMR-deficient cell line. RKO/CSCs overexpressed CD133 and MMR (hMSH2 and hMSH6) while SW480/CSCs showed a significantincrease in CD133, MMR (hMLH1, hMSH2 and hMSH6) and MGMT, moreover 5-FU resistance thanparental cell lines. Thus, although CSCs 5-FU chemoresistance appears to be independently to MMR status,hMLH1 might play a key role in CSC response to 5-FU. New drugs exploding these differences could benefitthe prognostic of patients with CRC.

    • Identification of PARP-1 in cancer stem cells of gastrointestinal cancers: A preliminary study

      QUIN˜ONERO ANA CEPERO DAVID URBANO JOSE´ A MUN˜ OZ-GA´ MEZ SANDRA M MARTI´N-GUERRERO DAVID MARTI´N-OLIVA JOSE PRADOS CONSOLACIO´ N MELGUIZO RAUL ORTIZ

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      Advanced-stage gastrointestinal tumors have high mortality due to chemotherapy limitations. One of thecauses of treatment failure is the presence of cancer stem cells (CSCs), which show resistance mechanismsagainst DNA damage, such as poly (adenosine diphosphate-ribose) polymerase 1 (PARP-1). However, little isknown about the relevance of PARP-1 in these tumor cells. Our purpose is to analyze the expression of PARP-1in cancer cells and CSCs from gastrointestinal tumors, its relationship with the DNA damage repair processand its modulation by cytotoxic and PARP-1 inhibitors. We used pancreatic, liver and colon cancer cell linesand isolated CSCs using Aldefluor technology to analyze PARP-1 expression. In addition, we examined theeffect of classic cytotoxic drugs (Doxorubicin, Gemcitabine, Irinotecan and 5-Fluorouracil) and a PARP-1inhibitor (Olaparib) in cultured cells and 3D tumorspheres. We demonstrated that PARP-1 is highly expressedin pancreatic, liver and colon tumor cells and that this expression was significantly higher in cell populationswith CSC characteristics. In addition, Doxorubicin and Gemcitabine increased their cytotoxic effect whenadministered simultaneously with Olaparib, decreasing the formation of 3D tumorspheres. Our findings suggestthat PARP-1 is a common and relevant resistance mechanism in CSCs from gastrointestinal tumors andthat the use of PARP-1 inhibitors may be an adjuvant therapy to increase apoptosis in this type of cells whichare responsible to cancer recurrence and metastasis.

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