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Purpose
Ra
diotherapy is integrate
d into the
multi
mo
dal treat
ment of localize
d hepatocellular carcino
ma (HCC) refractory to conventional treat
ment. Tu
mor control re
mains unsatisfactory an
d the sublethal effect associates with secon
dary sprea
d. The use of an effective
molecularly targete
d agent in co
mbination with ra
diotherapy is a potential therapeutic approach. Our ai
m was to assess the effect of co
mbining a phenylbutyrate-
derive
d histone
deacetylase (HDAC) inhibitor, AR-42, with ra
diotherapy in
m>in聽vitrom> an
d m>in聽vivom>
mo
dels of hu
man HCC.
Methods and Materials
Human HCC cell lines (Huh-7 and PLC-5) were used to evaluate the m>in聽vitrom> synergism of combining AR-42 with irradiation. Flow cytometry analyzed the cell cycle changes, whereas Western blot investigated the protein expressions after the combined treatment. Severe combined immunodeficient (SCID) mice bearing ectopic and orthotopic HCC xenografts were treated with AR-42 and/or radiotherapy for the m>in聽vivom> response.
Results
AR-42 significantly enhanced radiation-induced cell death by the inhibition of the DNA end-binding activity of Ku70, a highly versatile regulatory protein for DNA repair, telomere maintenance, and apoptosis. In ectopic xenografts of Huh-7 and PLC-5, pretreatment with AR-42 significantly enhanced the tumor-suppressive effect of radiotherapy by 48%and 66%, respectively. A similar combinatorial effect of AR-42 (10 and 25 mg/kg) and radiotherapy was observed in Huh-7 orthotopic model of tumor growth by 52%and 82%, respectively. This tumor suppression was associated with inhibition of intratumoral Ku70 activity as well as reductions in markers of HDAC activity and proliferation, and increased apoptosis.
Conclusion
AR-42 is a potent, orally bioavailable inhibitor of HDAC with therapeutic value as a radiosensitizer of HCC.