The results demonstrate that in renal cell carcinomas a significant relationship exists between resistance-related proteins, such as P-170, GST-pi, or Topo II, and proto-oncogenes, such as c-fos, c-erbB1, and c-neu.
The p-GSK3β (Ser9) protein level in Caki-2 cells was significantly down-regulated, while the DNA fragmentation rate increased after treatment with 5 μM DAC at 96 h. Our data show that sFRP2 functions as a tumor suppressor gene in RCC and that its restoration may offer a new therapeutic approach for the treatment of RCC.
Noticeably, elevated expression of ABCA13 and EZH2 is correlated with overall survival of RCC patients, which can be used as potential prognostic markers.
Genetic aberrations and reduced expression of ERC2 and ABCA13 were frequent in RCCs, and MTOR mutations were identified as one of the major disrupters of cell signaling during renal carcinogenesis.
Since these levels were lower than expected for RCC, we asked whether the metastases possessed a phenotype different from primary RCC and examined MDR-1 expression in 5 paired cell lines derived from primary and metastatic RCC.
Moreover, treatment of cultures with bleomycin or topotecan, a novel topoisomerase I inhibitor with little substrate affinity for P-glycoprotein, led to induction of apoptosis and significant (P < 0.05) dose-dependent reduction of cell number in all RCC cell lines.
All the N276 compounds also remarkably enhanced the sensitivity to VBL and DXR in both MDR1- and MRP-overexpressing renal cell carcinoma (RCC) cell line (NKK1), whereas they showed no potentiation of these anticancer agents in an RCC cell line (KPK1) expressing neither MDR1 nor MRP.
Expression of resistance factors (P-glycoprotein, glutathione S-transferase-pi, and topoisomerase II) and their interrelationship to proto-oncogene products in renal cell carcinomas.
Multidrug resistance in human renal cell carcinoma is mainly caused by expression of the MDR1 gene and is characterized by a broad spectrum cross resistance to many natural product chemotherapeutic agents.
Potential implications of this reduced mechanism of detoxification will be shown for three selected diseases: (1) association of low intestinal P-glycoprotein expression with development of inflammatory bowel disease; (2) implications for disease risk and therapeutic outcome of HIV; and (3) consequences of this mutation for renal P-glycoprotein expression and risk of renal cell carcinoma.
Renal cell carcinoma (RCC) ranks among the most chemoresistant tumors, and P-glycoprotein (P-gp) predominates multidrug resistance mechanisms by reducing the accumulation of intracellular chemotherapy drugs such as vinblastine (VBL), which is considered the most effective chemotherapeutic agent for this neoplasia.
Stage adjusted disease specific survival rate, according to MDR-1 expression and therapy in patients affected by RCC in early stage (stage I), has revealed that the group of patients with high MDR-1 expression and without adjuvant therapy showed poor survival (p < 0.05).
Enforced expression of the connexin (Cx) 32 gene, a member of the gap junction gene family and a tumor suppressor gene in human renal cell carcinoma (RCC), enhanced vinblastine (VBL)-induced cytotoxicity in RCC cells due to suppression of multidrug resistance 1 (MDR1) expression.
Mechanisms of chemoresistance in renal cell carcinoma include P-glycoprotein, overexpression of multidrug resistance-1 (mdr1) gene, and unstable chromosomal aberrations.
Surface expression of P-gp and VLA-1 to -6 was determined immunocytochemically in untreated pre-established renal carcinoma cell lines (Caki-1, Caki-2, A498) and a cell line derived from a RCC patient who had received a vinblastine-containing therapy regimen prior to the resection of a local relapse of the tumor (EH).