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Effect of new olivacine derivatives on p53 protein level
Tomasz Gębarowski1, Benita Wiatrak2, Katarzyna Gębczak1
1Department of Basic Medical Sciences, Wroclaw Medical University, Borowska 211, 50-556, Wrocław, Poland.
Background:
The p53 protein is a transcription factor for many genes, including genes involved in inhibiting cell proliferation and inducing apoptosis in genotoxically damaged and tumor-transformed cells. In more than 55% of cases of human cancers, loss of the essential function of p53 protein is found. In numerous reports, it has been shown that small molecules (chemical compounds) can restore the suppressor function of the mutant p53 protein in tumor cells. The aim of this study was to evaluate the potential anticancer activity of three newly synthesized olivacine derivatives.
Methods:
The study was performed using two cell lines-CCRF/CEM (containing the mutant p53 protein) and A549 (containing a non-mutant, wild-type p53 protein). The cells were incubated with olivacine derivatives for 18 h and then assays were carried out: measurement of the amount of p53 and p21 proteins, detection of apoptosis, cell cycle analysis, and rhodamine 123 accumulation assay (evaluation of P-glycoprotein inhibition). Multiple-criteria decision analysis was used to compare the anticancer activity of the tested compounds.
Results:
Each tested compound caused the reconstitution of suppressor activity of the p53 protein in cells with the mutant protein. In addition, one of the compounds showed significant antitumor activity in both wild-type and mutant cells. For all compounds, a stronger effect on the level of the p53 protein was observed than for the reference compound-ellipticine.
Conclusions:
The observed effects of the tested new olivacine derivatives (pyridocarbazoles) suggest that they are good candidates for new anticancer drugs.
Insights
New olivacine derivatives show promise as anticancer drugs by restoring the function of the p53 protein in cancer cells. One compound demonstrated significant antitumor activity in both mutant and wild-type p53 cell lines.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- The p53 protein is a critical tumor suppressor, and its loss of function is implicated in over 55% of human cancers.
- Small molecules are being investigated for their potential to restore mutant p53 suppressor activity in tumor cells.
Purpose of the Study:
- To evaluate the anticancer potential of three newly synthesized olivacine derivatives.
- To assess the ability of these compounds to restore p53 suppressor function in cancer cells.
Main Methods:
- Utilized CCRF/CEM (mutant p53) and A549 (wild-type p53) cell lines.
- Assessed p53 and p21 protein levels, apoptosis, cell cycle, and P-glycoprotein inhibition after compound incubation.
- Employed multiple-criteria decision analysis for compound comparison.
Main Results:
- All tested olivacine derivatives reconstituted p53 suppressor activity in mutant p53 cells.
- One derivative exhibited significant antitumor activity in both cell types.
- Compounds demonstrated a stronger effect on p53 levels compared to ellipticine.
Conclusions:
- The tested pyridocarbazole derivatives show potential as novel anticancer therapeutics.
- These compounds warrant further investigation for their clinical application in cancer treatment.
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