Targeting Hypoxic Cells through the DNA Damage Response

Abstract

Exposure to hypoxia-induced replication arrest initiates a DNA damage response that includes both ATR-and ATM-mediated signaling. DNA fiber analysis was used to show that these conditions lead to a replication arrest during both the initiation and elongation phases, and that this correlated with decreased levels of nucleotides. The DNA damage response induced by hypoxia is distinct from the classical pathways induced by damaging agents, primarily due to the lack of detectable DNA damage, but also due to the coincident repression of DNA repair in hypoxic conditions. The principle aims of the hypoxia-induced DNA damage response seem to be the induction of p53-dependent apoptosis or the preservation of replication fork integrity. The latter is of particular importance should reoxygenation occur. Tumor reoxygenation occurs as a result of spontaneous changes in blood flow and also therapy. Cells experiencing hypoxia and/or reoxygenation are, therefore, sensitive to loss or inhibition of components of the DNA damage response, including Chk1, ATM, ATR, and poly(ADP-ribose) polymerase (PARP). In addition, restoration of hypoxia-induced p53-mediated signaling may well be effective in the targeting of hypoxic cells. The DNA damage response is also induced in endothelial cells at moderate levels of hypoxia, which do not induce replication arrest. In this situation, phosphorylation of H2AX has been shown to be required for proliferation and angiogenesis and is, therefore, an attractive potential therapeutic target. Clin Cancer Res; 16(23); 5624-9. Ó2010 AACR.

Impact of Wee1 inhibition on the hypoxia-induced DNA damage response

“…For instance, we have previously demonstrated that inhibition or loss of the Chk1 or ATR increased sensitivity to hypoxia/ reoxygenation [11][12][13][14]. We propose therefore that, additional studies focused on components of the hypoxia-induced DDR have the potential to establish new therapeutic targets [13].…”

“…We propose therefore that, additional studies focused on components of the hypoxia-induced DDR have the potential to establish new therapeutic targets [13].…”

Radiation Resistance in Cancer Therapy: Meeting Summary and Research Opportunities Report of an NCI Workshop held September 1–3, 2010

“…ATM and ATR are activated, but without focus formation, consistent with the absence of strand breaks. Studies have demonstrated that hypoxia causes S-phase arrest and hinders the ability to restart replication in S-phase cells after prolonged hypoxia (2,3). Hypoxia also leads to substantially reduced dNTP pools via ribonucleotide reductase inhibition, accounting for the stalled replication (2,3).…”

“…Studies have demonstrated that hypoxia causes S-phase arrest and hinders the ability to restart replication in S-phase cells after prolonged hypoxia (2,3). Hypoxia also leads to substantially reduced dNTP pools via ribonucleotide reductase inhibition, accounting for the stalled replication (2,3). DNA repair pathways that are downregulated in hypoxia include DNA mismatch repair (MMR) and homology-directed repair (HDR) via specific transcriptional and post-transcriptional mechanisms (4,5).…”

RON Nuclear Translocation under Hypoxia Potentiates Chemoresistance to DNA Double-Strand Break–Inducing Anticancer Drugs

“…In addition, tumor hypoxia is a driving force of genetic instability and is pivotal in cancer development and chemoresistance (1,(21)(22)(23). Hypoxic cancer cells usually exhibit dysregulated DNA repair (24)(25)(26), but data conflict about the functional status of the NHEJ repair pathway under hypoxia (27)(28)(29). The molecular basis of DNA repair-mediated chemoresistance under hypoxia thus deserves further investigation.…”