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and it has been debated whether it directly induces DNA damage, but there is clear evidence that it triggers
DDR signaling and suppresses DNA repair [110,111] . Ultrasound waves generate heat, and this technology is
being explored to induce local hyperthermia for tumor radiosensitization [112] .

Radioprotectors and radiosensitizers
Because most radiation damage is induced indirectly through ROS, intrinsic and extrinsic modulation
of cellular re-dox status strongly affects radioresistance. Re-dox mechanisms have been investigated to
+
sensitize tumors and/or protect normal tissue during radiotherapy, including modulating NAD , glucose,
and other re-dox metabolic pathways; use of antioxidants (e.g., vitamins C and E) and isoflavones; use of
Mn-porphyrin compounds such as manganese-dependent superoxide dismutase (Mn-SOD) mimetics;
modulating superoxide dismutase; and modifying patient exercise routines [113-119] . Metformin, which
reduces hypoxia by reducing oxygen consumption, and melatonin, a natural hormone with antioxidant and
anti-inflammatory effects, are also under investigation for radiosensitization or protection [120-123] . Radiation
countermeasures are designed to protect individuals from adverse effects of accidental or intentional (i.e.,
dirty bomb) total-body irradiation; these strategies may be useful for normal tissue protection during
radiotherapy [124-126] .

Adaptive responses
Cells exposed to a low dose of radiation and then subsequently challenged by a high, cytotoxic dose
show enhanced survival compared to cells that did not receive a “priming” dose. This effect, termed
the adaptive response, typically refers to enhanced cell survival, but radioadaptive responses have been
observed with other endpoints, including chromosome aberrations, mutation, micronuclei formation, sister
chromatid exchange, delayed genome instability, and cellular transformation [127-133] . These radioadaptive
responses are transient, usually subsiding within 24 h of the priming dose. Several regulatory proteins are
known to positively or negatively influence cell survival adaptive responses to radiation, including Mn-
SOD, NFkB, p53, and NOX4, several of which are mediated by the anti-apoptosis factor survivin [134-139] .
Adaptive responses may be problematic, for example, if CT scans used to locate tumors induce tumor
radioresistance [134] , but other radioadaptive effects, such as immunomodulatory responses, may prove
beneficial [140,141] . These transient radioadaptive responses are distinct from two other types of tumor
adaptative responses to therapy: adaptive (upregulated) mutagenesis, which accelerates tumor evolution,
and modulation of tumor microenvironments, both of which can drive tumor resistance to radio- and
chemotherapy [142,143] .

TARGETING DSB REPAIR TO ENHANCE RADIOTHERAPY
DSB repair is a major determinant of cellular radioresistance, and key NHEJ and HR proteins are
attractive tumor radiosensitization targets. Because DNA repair and DDR systems are tightly integrated,
radiosensitization can be achieved by interfering with these networks in a multitude of ways. In addition,
[144]
“omics” analyses hold promise for personalizing radiotherapy doses based on radiation response profiles .
For additional perspectives on these topics, readers are referred to these recent reviews [31,35,97,145-149] . Current
experimental and therapeutic options that target DSB repair and DDR factors are listed in Table 1 and
discussed in the following sections.

TARGETING NHEJ
DNA-PKcs is activated when complexed with Ku-bound DNA ends at DSBs, leading to phosphorylation
of itself and other targets including Ku, RPA, and H2AX. DNA-PKcs autophosphorylation at two clusters
(ABCDE and PQR, including T2609 and T2056 residues) is critical for subsequent NHEJ steps [51,75,184] , and
DNA-PKcs inhibitors are strong radiosensitizers. However, because NHEJ is active in all nucleated cells,
and cells need to repair spontaneous DSBs, inhibiting NHEJ non-specifically may adversely affect normal