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Author Spotlight: Developing Novel Anticancer Therapeutics Targeting the DNA Damage Response
Published on: June 14, 2024
DNA-Damaging Anticancer Drugs - A Perspective for DNA Repair- Oriented Therapy
1Department of Molecular Genetics, University of Lodz, Lodz, Poland.
Abstract:
DNA-damaging drugs in cancer present two main problems: therapeutic resistance and side effects and both can associate with DNA repair, which can be targeted in cancer therapy. Bleomycin (BLM) induces complex DNA damages, including strand breaks, base loss and 3'-phosphoglycolate (3'PG) residues repaired by several pathways, but 3'PGs must be processed to the 3'-OH ends, usually by tyrosyl-DNA phosphodiesterase 1 (Tdp1). Therefore, targeting Tdp1 can improve anticancer therapy with BLM. Mitomycin C (MMC) produces a variety of adducts with DNA, including inter-strand cross-links (ICLs) and Xeroderma pigmentosum (XP) proteins, including XPG, XPE and XPF can be crucial for the initial stage of ICL repair, so they can be targeted by inhibitors to increase toxicity of MMC in cancer cells. Although these proteins are essential for nucleotide excision repair (NER), their decreased activity may not be fatal in normal cells as almost all NER substrates can be repaired by other pathways. Four-stranded DNA, resulted mainly from guanine quadruplexes (G-4s), are highly overexpressed at the end of telomeres, where they can inhibit telomerase, hence stabilization G-4s at the telomeres ends can hamper proliferation of cancer cells. Quadruplexes are also found in the promoters of genes important for cancer and are resolved by DNA helicases, which can be targeted in cancer along with stabilization of quadruplexes. As cancer cells often have defects in DNA repair pathway(s), they can be subjected by synthetic lethality, with the most promising results with poly(ADP-ribose) polymerase 1 (PARP-1) and DNA-dependent protein kinase, catalytic subunit (DNA-PKCS).
Insights
Targeting DNA repair pathways, like Tdp1 for Bleomycin and XP proteins for Mitomycin C, can enhance cancer therapy. Stabilizing guanine quadruplexes and exploiting synthetic lethality with PARP-1 also show promise.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- DNA-damaging cancer drugs face challenges of therapeutic resistance and side effects, often linked to DNA repair mechanisms.
- Specific DNA damages induced by drugs like Bleomycin (BLM) and Mitomycin C (MMC) involve complex lesions requiring distinct repair pathways.
Purpose of the Study:
- To explore targeting DNA repair pathways for improved cancer therapy efficacy.
- To identify specific enzymes and DNA structures that can be targeted to enhance the toxicity of DNA-damaging agents or inhibit cancer cell proliferation.
Main Methods:
- Investigating the role of tyrosyl-DNA phosphodiesterase 1 (Tdp1) in repairing Bleomycin-induced DNA damage.
- Examining the involvement of Xeroderma pigmentosum (XP) proteins (XPG, XPE, XPF) in Mitomycin C-induced inter-strand cross-link (ICL) repair.
- Analyzing the potential of targeting guanine quadruplexes (G-4s) and DNA helicases in cancer therapy.
- Exploring synthetic lethality strategies, particularly involving poly(ADP-ribose) polymerase 1 (PARP-1) and DNA-dependent protein kinase, catalytic subunit (DNA-PKCS).
Main Results:
- Inhibition of Tdp1 could enhance the efficacy of Bleomycin therapy by preventing the repair of 3'-phosphoglycolate (3'PG) residues.
- Targeting XP proteins involved in ICL repair could increase Mitomycin C's toxicity in cancer cells, with potentially less impact on normal cells.
- Stabilizing G-4s at telomeres or in gene promoters, and inhibiting DNA helicases, may impede cancer cell proliferation.
- Exploiting DNA repair defects in cancer cells through synthetic lethality with PARP-1 and DNA-PKCS inhibitors shows significant promise.
Conclusions:
- Targeting specific DNA repair enzymes and pathways offers a viable strategy to overcome therapeutic resistance and reduce side effects in cancer treatment.
- Exploiting the unique DNA structures like G-4s and leveraging synthetic lethality in cancer cells with DNA repair deficiencies represent promising avenues for novel cancer therapies.
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