The poor survival of patients with
malignant gliomas, underscores the need to develop effective treatment modalities for this devastating disease. Epigenetic agents used in combination with
chemotherapy provide a promising approach to evoke synergistic cytotoxicity in
glioblastomas. Previously we have described the cytotoxic synergy between a
butyric acid prodrug and radiation in
glioblastoma cell lines and the potentiation of radiation efficacy in
glioma xenografts. Herein, we describe and compare the activities of AN446 (valproyl
ester-valpramide of
acyclovir) a novel
histone deacetylase inhibitor (HDACI) to the previously described AN7 a HDACI
prodrug of
butyric acid. In various
cancer cell lines, AN446 was a ~2-5-fold more potent
anticancer agent HDACI than AN7. While AN446 augmented the anticancer efficacy of
doxorubicin (Dox) it also reduced the Dox toxicity in non-cancerous cells. The interaction between AN446 and Dox in U251 and in 4T1 cell lines was synergistic in inducing cytotoxicity. We examined the concomitant physical and molecular changes in the
tumor and heart of
glioblastoma xenografts treated with AN446, AN7, Dox and the combination of the
prodrugs with Dox. A weekly dose of 4 mg/kg Dox, caused toxicity in mice whereas AN446 (25mg/kg) or AN7 (50mg/kg) administered thrice weekly, did not. When Dox was administered with AN446 or AN7, the
prodrugs ameliorated the decline in
body weight, prolonged the time to failure and increased anticancer efficacy. Thus, the combination of Dox with AN446 or AN7 could add safety and efficacy to future treatment protocols for treating
glioblastoma and other
cancers.