Contributions
Abstract: PB1655
Type: Publication Only
Background
The interweaving between telomerase and immortalization of tumor cells steered treatment strategies into an endless path of targeted therapies. For the nonce and among the overabundance of promising inhibitors, exploitation of potent molecules targeting telomerase turns to be intensively encouraging.
Aims
To assess the anti-tumor effect of telomerase inhibition in cancer, a panel of human tumor cells spanning from solid tumors to hematologic malignancies was treated with the different concentrations of small molecule inhibitor of hTERT, BIBR1532.
Methods
MTT, Trypan blue, annexin/PI staining, cell cycle analysis, caspase-3 activity, and cell-based NF-κB phosphorylation assays coupled with analysis of gene expression by using quantitative real-time PCR were applied to examine the effects and molecular mechanisms of action of BIBR1532.
Results
We found that BIBR1532 exerted a potent cytotoxic effect on all the tested human cancer cells; however, as compared with leukemic cells, solid tumor cells were more resistant to the inhibitor. By investigating the relative sensitivity of leukemic cells to BIBR1532, we failed to identify any relationship between p53 status and cell response to the inhibitor. Our results also indicated that telomerase inhibition using BIBR1532 resulted in a considerable growth suppressive effect in APL-derived NB4 cells, as the most sensitive cell line, mostly through p21-mediated G1 arrest coupled with a caspase-3-dependent apoptosis via suppression of NF-κB. Moreover, the resulting data showed that combination of BIBR1532 and ATRA produced synergistic anticancer effects in mutant p53-expressing NB4 cells.
Conclusion
Our study not only indicated the potential application of BIBR1532 in both wild-type and deficient p53-expressing cells but also outlined the therapeutic efficacy of the inhibitor as either single agent or in combination with ATRA in APL.
Session topic: 3. Acute myeloid leukemia - Biology & Translational Research
Keyword(s): APL, NF- B, P53, Telomerase
Abstract: PB1655
Type: Publication Only
Background
The interweaving between telomerase and immortalization of tumor cells steered treatment strategies into an endless path of targeted therapies. For the nonce and among the overabundance of promising inhibitors, exploitation of potent molecules targeting telomerase turns to be intensively encouraging.
Aims
To assess the anti-tumor effect of telomerase inhibition in cancer, a panel of human tumor cells spanning from solid tumors to hematologic malignancies was treated with the different concentrations of small molecule inhibitor of hTERT, BIBR1532.
Methods
MTT, Trypan blue, annexin/PI staining, cell cycle analysis, caspase-3 activity, and cell-based NF-κB phosphorylation assays coupled with analysis of gene expression by using quantitative real-time PCR were applied to examine the effects and molecular mechanisms of action of BIBR1532.
Results
We found that BIBR1532 exerted a potent cytotoxic effect on all the tested human cancer cells; however, as compared with leukemic cells, solid tumor cells were more resistant to the inhibitor. By investigating the relative sensitivity of leukemic cells to BIBR1532, we failed to identify any relationship between p53 status and cell response to the inhibitor. Our results also indicated that telomerase inhibition using BIBR1532 resulted in a considerable growth suppressive effect in APL-derived NB4 cells, as the most sensitive cell line, mostly through p21-mediated G1 arrest coupled with a caspase-3-dependent apoptosis via suppression of NF-κB. Moreover, the resulting data showed that combination of BIBR1532 and ATRA produced synergistic anticancer effects in mutant p53-expressing NB4 cells.
Conclusion
Our study not only indicated the potential application of BIBR1532 in both wild-type and deficient p53-expressing cells but also outlined the therapeutic efficacy of the inhibitor as either single agent or in combination with ATRA in APL.
Session topic: 3. Acute myeloid leukemia - Biology & Translational Research
Keyword(s): APL, NF- B, P53, Telomerase