Dihydropyrimidine Dehydrogenase Levels in Colorectal Cancer Cells Treated with a Combination of Heat Shock Protein 90 Inhibitor and Oxaliplatin or Capecitabine

Abstract

Purpose: Dihydropyrimidine dehydrogenase (DPD) is the principal enzyme in the catabolism of fluoropyrimidine drugs including capecitabine. A recent report has suggested that oxaliplatin chemotherapy is associated with elevated DPD levels and chemoresistance pattern. As a newly developed chemotherapeutic agent, 17-allyloamino-17-demethoxy-geldanamycin (17-AAG) can be effective in combination therapy with oxaliplatin and capecitabine in colorectal cancer (CRC). DPD expression level can be a predictive factor in oxaliplatin and capecitabine-based chemotherapy. We evaluated DPD in mRNA and protein levels with new treatments: 17-AAG in combination with oxaliplatin and capecitabine in HT-29 and HCT-116 cell lines. Methods: Drug sensitivity was determined by the water-soluble tetrazolium-1 assay in a previous survey. Then, we evaluated the expression levels of DPD and its relationship with the chemotherapy response in capecitabine, oxaliplatin, and 17-AAG treated cases in single and combination cases in two panels of CRC cell lines. DPD gene and protein expression levels were determined by real-time polymerase chain reaction and western blotting assay, respectively. Results: DPD gene expression levels insignificantly increased in single-treated cases versus untreated controls in both cell lines versus controls. Then, the capecitabine and oxaliplatin were added in double combinations, where DPD gene and protein expression increased in combination cases compared to pre-chemotherapy and single drug treatments. Conclusion: The elevated levels of cytotoxicity in more effective combinations could be related to a different mechanism apart from DPD mediating effects or high DPD level in the remaining resistance cells (drug-insensitive cells), which should be investigated in subsequent studies.

HSP90α Mediates Sorafenib Resistance in Human Hepatocellular Carcinoma by Necroptosis Inhibition Under Hypoxia

“…Combination of 17-AAG and oxaliplatin or capecitabine in colorectal cancer cell lines has been studied. 17-AAG in combination with paclitaxel on anaplastic thyroid carcinoma cells has also been reported [29][30][31]. In this study, we con rmed that necroptosis was one of the important reasons of Sorafenib attacking HCC.…”

HSP90α Mediates Sorafenib Resistance in Human Hepatocellular Carcinoma by Necroptosis Inhibition under Hypoxia

“…The combination of 17-AAG and oxaliplatin or capecitabine in colorectal cancer cell lines has been studied. 17-AAG in combination with paclitaxel on anaplastic thyroid carcinoma cells has also been reported [ 28 , 29 , 30 ]. In this study, we confirmed that necroptosis was one of the important reasons why Sorafenib attacks HCC.…”

Regulatory Effects of Apatinib in Combination with Piperine on MDM-2 Gene Expression, Glutathione Peroxidase Activity and Nitric Oxide level as Mechanisms of Cytotoxicity in Colorectal Cancer Cells

“…Colorectal cancer (CRC) is the third-largest cancer world width 1,2 and is related to a high rate of mortality. [1][2][3][4][5] Recently, clinical studies have been interested in detecting novel integrating targeted treatments and combination chemotherapy regimens. 2 Combination chemotherapy comes into importance in CRC treatment but drug resistance is inevitable.…”

“…3 In this regard, evaluating new drug combinations can improve the treatment outcomes. 3,5 Numerous efforts have been conducted for increase understanding of the CRC heterogeneity and propose the most effective-tailored treatment to any affected patient. 6 Since, oncogene mutations and the existence of multi-drug resistance, and the intolerable side effects limit the efficiency of treatment.…”