Differential sensitivity of renal carcinoma cells to doxorubicin and epigenetic therapeutics depends on the genetic background
Differential sensitivity to chemotherapeutics is a limitation in chemotherapy of kidney cancer patients. Role of genetic background in chemotherapy is not fully understood. Therefore, this study evaluated the influence of genetic/epigenetic background of renal cancer cells on the sensitivity to chem...
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Published in | Molecular and cellular biochemistry Vol. 476; no. 6; pp. 2365 - 2379 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
New York
Springer US
01.06.2021
Springer Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | Differential sensitivity to chemotherapeutics is a limitation in chemotherapy of kidney cancer patients. Role of genetic background in chemotherapy is not fully understood. Therefore, this study evaluated the influence of genetic/epigenetic background of renal cancer cells on the sensitivity to chemotherapeutics. Two renal cell carcinoma (RCC) cell lines, Caki-1 and 786-0, with different genetic makeup of
p53
and
VHL
were treated with doxorubicin either alone or in combination with epigenetic therapeutics 5-aza-2-dc and TSA. Sensitivity of RCC cells to these drugs was evaluated by cell viability and cell cycle analysis and was further confirmed by analysis of selected genes expression. Cell viability data revealed that 786-0 cells were more sensitive than Caki-1 to doxorubicin. Combination of doxorubicin with 5-aza-2-dc or TSA was more effective to inhibit growth of Caki-1 cells but not the 786-0. Data of cell cycle analysis and expression of representative genes for tumor suppressor, cell cycle and survival, drug transporter and DNA repair further provided the molecular basis for differential sensitivity of Caki-1 and 786-0 cell lines to doxorubicin. Important findings of this study suggest that doxorubicin is more cytotoxic to primary renal cancer 786-0 cells with mutant
VHL
and
p53
than the metastatic Caki-1 cells with wild-type
VHL
and
p53
, and this differential response was independent of
p53
expression level. This study suggests that combination of doxorubicin with epigenetic therapeutics could potentially be beneficial in clinical treatment of renal cancer patients with wild-type
VHL
and
p53
but not in patients with mutant
VHL
and
p53
. |
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ISSN: | 0300-8177 1573-4919 |
DOI: | 10.1007/s11010-021-04076-7 |