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Antitumor activity of TMPyP4 interacting G-quadruplex in retinoblastoma cell lines
Yoko Mikami-Terao1, Masaharu Akiyama, Yuki Yuza
1Department of Pediatrics, Jikei University School of Medicine, Tokyo 105-8461, Japan.
Abstract:
To investigate the molecular mechanism of the antitumor activity of the cationic porphyrin 5, 10, 15, 20-tetra-(N-methyl-4-pyridyl)porphyrin (TMPyP4) in retinoblastoma cell lines, Y79 and WERI-Rb1 cells were treated with TMPyP4 for 0-72 h, after which growth inhibition, modulation of the cell cycle and the induction of apoptosis were examined. In addition, the effect of TMPyP4 on the susceptibility to irradiation was evaluated in Y79 and WERI-Rb1 cells. In vitro telomeric repeat amplification protocol assay showed TMPyP4 (10-100 microM) directly blocked telomerase elongation, suggesting that TMPyP4 can form stable guanine (G)-quadruplexes in extending telomere repeats in substrate oligonucleotides. The antiproliferative activities of TMPyP4 assessed with the MTS assay and expressed in terms of IC(50): Y79 cells, 60 microM; WERI-Rb1 cells, 45 microM. Treatment with TMPyP4 at doses of 10, 20, 50 or 100 microM for 48 or 72 h significantly inhibited the growth of Y79 and WERI-Rb1 cells. Apoptosis, as assessed with CaspACE FITC-VAD-FMK, was induced by TMPyP4 in a dose-dependent manner. Induction of apoptosis by TMPyP4 was associated with increased expression of phosphorylated DNA damage response factor H2AX (Ser139), phosphorylated p53 (Ser46) protein and activation of mitogen-activated protein kinases in Y79 and WERI-Rb1 cells. Moreover, TMPyP4 significantly enhanced the susceptibility to irradiation in both cell lines. This study provides insight into the molecular mechanism of the antitumor effects of TMPyP4. G-quadruplex structure may be a potential therapeutic target in retinoblastoma.
Insights
The cationic porphyrin 5, 10, 15, 20-tetra-(N-methyl-4-pyridyl)porphyrin (TMPyP4) inhibits retinoblastoma cell growth by blocking telomerase and inducing apoptosis. TMPyP4 also increases sensitivity to radiation, suggesting G-quadruplex structures as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Retinoblastoma is a pediatric eye cancer with limited treatment options.
- Cationic porphyrins are being investigated for their potential antitumor activities.
- Understanding the molecular mechanisms of drug action is crucial for developing effective therapies.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying the antitumor effects of 5, 10, 15, 20-tetra-(N-methyl-4-pyridyl)porphyrin (TMPyP4) in retinoblastoma cell lines.
- To evaluate the impact of TMPyP4 on cell proliferation, cell cycle, apoptosis, and radiosensitivity.
- To explore the potential of G-quadruplex structures as therapeutic targets in retinoblastoma.
Main Methods:
- Cell viability and proliferation assays (MTS assay) were performed on Y79 and WERI-Rb1 retinoblastoma cells.
- Telomerase activity was assessed using the in vitro telomeric repeat amplification protocol (TRAP) assay.
- Apoptosis was quantified using CaspACE FITC-VAD-FMK, and protein expression (phosphorylated H2AX, p53, MAPKs) was analyzed.
- Cells were also treated with TMPyP4 and irradiation to evaluate radiosensitivity.
Main Results:
- TMPyP4 demonstrated antiproliferative activity against retinoblastoma cells with IC(50) values of 60 microM (Y79) and 45 microM (WERI-Rb1).
- TMPyP4 directly inhibited telomerase elongation by forming stable G-quadruplexes, suggesting a novel mechanism of action.
- TMPyP4 induced apoptosis in a dose-dependent manner, associated with increased DNA damage markers and MAPK activation.
- TMPyP4 significantly enhanced the radiosensitivity of both retinoblastoma cell lines.
Conclusions:
- TMPyP4 exhibits significant antitumor effects in retinoblastoma cells through telomerase inhibition and apoptosis induction.
- The formation of G-quadruplex structures by TMPyP4 is a key molecular mechanism contributing to its anticancer activity.
- TMPyP4 holds promise as a therapeutic agent for retinoblastoma, potentially in combination with radiotherapy.
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