Targeting Base Excision Repair for Chemosensitization

Abstract

In both bacteria and eukaryotes the alkylated, oxidized, and deaminated bases and depurinated lesions are primarily repaired via an endogenous preventive pathway, i.e. base excision repair (BER). Radiation therapy and chemotherapy are two important modes of cancer treatment. Many of those therapeutic agents used in the clinic have the ability to induce the DNA damage; however, they may also be highly cytotoxic, causing peripheral toxicity and secondary cancer as adverse side effects. In addition, the damage produced by the therapeutic agents can often be repaired by the BER proteins, which in effect confers therapeutic resistance. Efficient inhibition of a particular BER protein(s) may increase the efficacy of current chemotherapeutic regimes, which minimizes resistance and ultimately decreases the possibility of the aforementioned negative side effects. Therefore, pharmacological inhibition of DNA damage repair pathways may be explored as a useful strategy to enhance chemosensitivity. Various agents have shown excellent results in preclinical studies in combination chemotherapy. Early phase clinical trials are now being carried out using DNA repair inhibitors targeting enzymes such as PARP, DNA-PK or MGMT. In the case of BER proteins, elimination of N-Methylpurine DNA glycosylase (MPG) or inhibition of AP-endonuclease (APE) increased sensitivity of cancer cells to alkylating chemotherapeutics. MPG(-/-) embryonic stem cells and cells having MPG knock-down by siRNA are hypersensitive to alkylating agents, whereas inhibition of APE by small molecule inhibitors sensitized cancer cells to alkylating chemotherapeutics. Thus, MPG and other BER proteins could be potential targets for chemosensitization.

Impact of microRNAs in Resistance to Chemotherapy and Novel Targeted Agents in Non-Small Cell Lung Cancer

“…Furthermore, approximately 70% of patients resistant to gefitinib and erlotinib, EGFR tyrosine kinase inhibitors (TKIs), have the secondary EGFR T790M mutation or the amplification of c-Met [10]. In some cases, drug resistance in tumors, including NSCLC, may be due to defects in DNA-repair pathways, such as nucleotide excision-repair (NER) [11,12], mismatch-repair (MMR) [13], base excision-repair (BER) [14], non-homologous endjoining (NHEJ) [15] and homologous-recombination (HR) [16]. Moreover, it is important to emphasize that the loss of intracellular death mechanisms, including apoptotic pathways, causes tumor cell survival and cancer progression by making the cells resistant to therapeutic agents [17].…”

The C-terminal Domain (CTD) of Human DNA Glycosylase NEIL1 Is Required for Forming BERosome Repair Complex with DNA Replication Proteins at the Replicating Genome

“…Their repair, which contributes to drug resistance, depends on BER competency of the cells. Thus, various strategies to target the BER pathway are being explored for sensitizing cancer cells as an adjuvant therapy modality with radiation or radiomimetic drugs (2)(3)(4).…”

Base Excision Repair Manipulation in Breast Carcinoma: A Prospective Avenue to Potentiate Genome Insulting Approach

“…Methoxyamine inhibits the repair of AP sites by binding to and modifying the AP site, rather than directly inhibiting the enzyme APE1 [83]. Inhibition of AP-endonuclease (APE) lead to increased sensitivity of cancer cells to alkylating chemotherapeutics [84]. When AP-sites are oxidized or reduced, they become resistant to elimination and cannot be excised by the dRP lyase activity of pol [85].…”