Assessment of HDAC activity and therapeutic effect of HDAC inhibitor in hepatoma by [¹⁸F]FAHA PET imaging

Objectives Histone deacetylase inhibitor (HDACI) has been widely used in treatment of hematologic malignancy and solid tumors. This study aimed to evaluate the HDAC expression and therapeutic response of hepatocellular carcinoma (HCC) to HDACI by [F-18]-6-(fluoroacetamide)-1-hexanoicanilide (FAHA) PET.

Methods Huh 7 cells (human hepatoma cell line) were transfected with p21-3H+ptK-Rluc. 5x10⁶ cells mixed with 50uL serum free media and 50uL metrigel were inoculated subcutaneously on the left shoulder of 8-10 week-old male BalbC/Nu mice. All animals received baseline [¹⁸F]FAHA PET imaging at 22 days after xenograft. To evaluate the immediate effect of HDACI, we performed [¹⁸F]FAHA PET imaging 60 min after intraperitoneal administration of SAHA (50 mg/kg). The HDACI treatment continued for 7 days and the end point was assessed by [¹⁸F]FAHA imaging and by measurement of the change of tumor size (Tumor size: length x width x height x 0.523 mm³). Dynamic PET imaging was performed for 20 min after i.v. administration of 18.5 MBq of [¹⁸F]FAHA. Tomographic images were reconstructed by OSEM+MAP and analyzed by ASIPro VM 6.3.3.0. SUVs of [¹⁸F]FAHA were measured from the ROIs in the tumor and the contralateral normal soft tissue. Tumor-to-muscle ratios (T/M) of SUVs obtained from the animals with or without SAHA treatment were compared.

Results SAHA revealed no significant effect to inhibit the tumor growth. All tumors demonstrated avid uptake of FAHA (SUV: 1.2±0.4). No obvious change of SUV was observed in mice without SAHA treatment and in mice with 7-day regimen of SAHA treatment. However, there was 33% to 60% decrease of FAHA uptake by the tumor at 60 min after SAHA treatment.

Conclusions [¹⁸F]FAHA PET imaging is useful for monitoring of HDAC activity during HDACI treatment of hepatoma. Hu7 hepatoma express HDAC activity, but no obvious therapeutic effect of HDACI (SAHA) alone was observed in this study. SAHA has transient effect on suppression of HDAC activity in hepatoma