Ionizing radiation enhances adenoviral vector expressing mda-7/IL-24-mediated apoptosis in human ovarian cancer
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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Luni Emdad1, Devanand Sarkar, Irina V Lebedeva
1Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York 10032, USA.
Abstract:
Ovarian cancer is the fifth most common cause of cancer-related death in women. Current interventional approaches, including debulking surgery, chemotherapy, and/or radiation have proven minimally effective in preventing the recurrence and/or mortality associated with this malignancy. Subtraction hybridization applied to terminally differentiating human melanoma cells identified melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), whose unique properties include the ability to selectively induce growth suppression, apoptosis, and radiosensitization in diverse cancer cells, without causing any harmful effects in normal cells. Previously, it has been shown that adenovirus-mediated mda-7/IL-24 therapy (Ad.mda-7) induces apoptosis in ovarian cancer cells, however, the apoptosis induction was relatively low. We now document that apoptosis can be enhanced by treating ovarian cancer cells with ionizing radiation (IR) in combination with Ad.mda-7. Additionally, we demonstrate that mda-7/IL-24 gene delivery, under the control of a minimal promoter region of progression elevated gene-3 (PEG-3), which functions selectively in diverse cancer cells with minimal activity in normal cells, displays a selective radiosensitization effect in ovarian cancer cells. The present studies support the use of IR in combination with mda-7/IL-24 as a means of augmenting the therapeutic benefit of this gene in ovarian cancer, particularly in the context of tumors displaying resistance to radiation therapy.
Insights
Combining ionizing radiation (IR) with melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) therapy enhances ovarian cancer cell apoptosis. This combination, utilizing a cancer-selective promoter, improves therapeutic outcomes, especially for radiation-resistant tumors.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Ovarian cancer is a leading cause of cancer death in women, with limited success in preventing recurrence and mortality with current treatments.
- Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) exhibits selective anti-cancer properties, including growth suppression and apoptosis induction.
- Previous adenovirus-mediated mda-7/IL-24 (Ad.mda-7) therapy showed limited apoptosis induction in ovarian cancer cells.
Purpose of the Study:
- To investigate the synergistic effect of ionizing radiation (IR) and Ad.mda-7 on ovarian cancer cell apoptosis.
- To evaluate the efficacy of mda-7/IL-24 gene delivery using a cancer-selective minimal promoter (PEG-3) for radiosensitization.
- To support the combined use of IR and mda-7/IL-24 for improved ovarian cancer therapy.
Main Methods:
- Treatment of ovarian cancer cells with Ad.mda-7 in combination with IR.
- Gene delivery of mda-7/IL-24 under the control of the PEG-3 minimal promoter.
- Assessment of apoptosis induction and radiosensitization effects.
Main Results:
- Combining Ad.mda-7 with IR significantly enhanced apoptosis in ovarian cancer cells compared to Ad.mda-7 alone.
- The PEG-3 promoter facilitated cancer-selective mda-7/IL-24 expression and radiosensitization.
- The combination therapy demonstrated augmented therapeutic benefits, particularly in radiation-resistant ovarian cancer models.
Conclusions:
- Ionizing radiation combined with mda-7/IL-24 therapy offers a promising strategy to enhance apoptosis and overcome resistance in ovarian cancer.
- Cancer-selective gene delivery of mda-7/IL-24, controlled by the PEG-3 promoter, represents a targeted approach for ovarian cancer treatment.
- This approach holds potential for improving therapeutic outcomes in ovarian cancer patients, especially those with radioresistant disease.
