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Published on: July 25, 2020
Radiosensitization by antisense anti-MDM2 mixed-backbone oligonucleotide in in vitro and in vivo human cancer models
Zhuo Zhang1, Hui Wang, Gautam Prasad
1Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA.
Purpose:
The MDM2 oncogene, amplified or overexpressed in many human cancers, has been suggested to be a novel target for cancer therapy. We have demonstrated a second-generation antisense antihuman-MDM2 oligonucleotide to have antitumor activity when administered alone or in combination with cancer chemotherapeutic agents. In the present study, we investigated the effect of the antisense oligonucleotide on radiation therapy.
Experimental Design:
The in vitro radiosensitization activity was determined in cell lines of human cancers of prostate (LNCaP and PC3), breast (MCF-7 and MDA-MB-468), pancreas (PANC-1), and glioma (U87-MG and A172) and its in vivo radiosensitization activity in xenograft models of LNCaP, PC3, MCF-7, MDA-MB-468, and PANC-1.
Results:
In cells containing at least one functional p53 allele (LNCaP, U87-MG, and A172), after specific inhibition of MDM2 expression, p53 and p21 levels were elevated. In LNCaP cells, the Bax level was increased, and Bcl-2 and E2F1 levels were decreased. In PC3 cells that are p53 null, after inhibition of MDM2 expression, Bax and p21 levels were elevated, and E2F1 levels were decreased. On the basis of in vitro clonogenic assay, the antisense oligonucleotide, in a sequence-specific manner, significantly increased radiation-induced antiproliferation effects. It also increased radiation-induced inhibitory effects on tumor growth in SCID or nude mice bearing LNCaP, PC3, MCF-7, MDA-MB-468, and PANC-1 xenografts.
Conclusions:
These results suggest that MDM2 has a role in radiation therapy of human cancers, regardless of p53 status, providing a basis for future development of MDM2 inhibitors, such as antisense oligonucleotides, as radiosensitizers.
Insights
This study shows that an antisense oligonucleotide targeting MDM2 enhances radiation therapy effectiveness in various human cancer cells and tumors. This MDM2 inhibition boosts anti-cancer effects regardless of p53 status, supporting its use as a radiosensitizer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The MDM2 oncogene is frequently amplified or overexpressed in human cancers.
- MDM2 is a potential therapeutic target for cancer treatment.
- Antisense antihuman-MDM2 oligonucleotide demonstrates antitumor activity.
Purpose of the Study:
- To investigate the effect of an antisense oligonucleotide targeting MDM2 on radiation therapy.
- To evaluate the radiosensitizing potential of MDM2 inhibition in various human cancer types.
Main Methods:
- In vitro radiosensitization assays using human cancer cell lines (prostate, breast, pancreas, glioma).
- In vivo studies using xenograft models of human cancers in mice.
- Analysis of molecular markers including p53, p21, Bax, and Bcl-2 levels.
Main Results:
- MDM2 inhibition elevated p53 and p21 levels in p53-proficient cells and Bax and p21 in p53-null cells.
- The antisense oligonucleotide significantly enhanced radiation-induced antiproliferation in vitro.
- Radiation therapy combined with MDM2 inhibition reduced tumor growth in vivo across multiple cancer xenografts.
Conclusions:
- MDM2 plays a role in the response to radiation therapy in human cancers, irrespective of p53 status.
- Antisense oligonucleotides targeting MDM2 show promise as radiosensitizers.
- These findings support the development of MDM2 inhibitors for combination cancer therapy.
