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Published on: January 9, 2020
Inhibition of oral cancer cell growth by adenovirusMnSOD plus BCNU treatment
Christine J Darby Weydert1, Benjamin B Smith, Linjing Xu
1Free Radical and Radiation Biology Program, Department of Radiation Oncology, Roy J. and Lucille A. Carver College of Medicine and Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
Abstract:
We hypothesized that inhibitors of peroxide removal, such as BCNU, an indirect inhibitor of glutathione peroxidase (GPx), and 3-amino-1,2,4-triazole (AT), a direct inhibitor of catalase (CAT), should cause toxicity to cancer cells after manganese superoxide dismutase (MnSOD) overexpression due to elevated peroxide levels. In vitro, hamster cheek pouch carcinoma cells (HCPC-1) and human oral squamous carcinoma cells (SCC-25) were infected with various combinations of adenovirus containing MnSOD cDNA (AdMnSOD). Cells were then treated with or without BCNU and assayed for viability using Annexin/PI staining and flow cytometry. In AdMnSOD plus BCNU-treated SCC-25 and HCPC-1 cells, a 30-60% decrease in cell viability was observed compared to BCNU alone. In vivo, HCPC-1 and SCC-25 xenografts were allowed to grow to approximately 70 mm(3) and 10(9) plaque forming units (pfu) of AdMnSOD were injected directly into the tumors. Two days later, 15 or 30 mg/kg BCNU was injected intratumorally. Tumor growth was greatly inhibited (4- to 20-fold) by this combined treatment, as well as increasing animal survival. Tumor volume could be decreased further by giving multiple doses of AdMnSOD or inhibiting catalase activity with AT. These results suggest that, by using these combination therapies, a significant decrease in tumor mass can be achieved.
Insights
Overexpressing manganese superoxide dismutase (MnSOD) in cancer cells sensitizes them to peroxide-elevating chemotherapy. This combination therapy significantly inhibited tumor growth and increased survival in preclinical models.
Area of Science:
- Oncology
- Biochemistry
- Gene Therapy
Background:
- Elevated reactive oxygen species (ROS) and peroxide levels are implicated in cancer progression.
- Manganese superoxide dismutase (MnSOD) plays a crucial role in scavenging superoxide radicals.
- Inhibiting peroxide-scavenging enzymes can potentiate oxidative stress in cancer cells.
Purpose of the Study:
- To investigate the synergistic effect of manganese superoxide dismutase (MnSOD) overexpression and peroxide-elevating chemotherapy on cancer cell toxicity.
- To evaluate the therapeutic potential of combining AdMnSOD gene therapy with BCNU in preclinical cancer models.
Main Methods:
- In vitro studies using human oral squamous carcinoma (SCC-25) and hamster cheek pouch carcinoma (HCPC-1) cells infected with AdMnSOD.
- In vivo studies using SCC-25 and HCPC-1 xenografts treated with AdMnSOD and BCNU.
- Cell viability assays (Annexin/PI staining, flow cytometry) and tumor growth inhibition measurements.
Main Results:
- Combined AdMnSOD and BCNU treatment resulted in a 30-60% decrease in cancer cell viability in vitro.
- Intratumoral AdMnSOD combined with BCNU significantly inhibited tumor growth (4- to 20-fold) and improved animal survival in vivo.
- Further tumor reduction was achieved by multiple AdMnSOD doses or catalase inhibition with 3-amino-1,2,4-triazole (AT).
Conclusions:
- Overexpression of MnSOD enhances cancer cell susceptibility to chemotherapy agents that increase peroxide levels.
- Combination therapy involving MnSOD overexpression and BCNU demonstrates significant anti-tumor efficacy in preclinical settings.
- Targeting peroxide metabolism pathways alongside MnSOD offers a promising strategy for cancer treatment.
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