An anti-cancer derivative of butyric acid (pivalyloxmethyl buterate) and daunorubicin cooperatively prolong survival of mice inoculated with monocytic leukaemia cells

Kasukabe, Takashi; Rephaeli, Ada; Honma, Yoshio

doi:10.1038/bjc.1997.151

Cited by 35 publications

(42 citation statements)

References 17 publications

(22 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pivaloyloxymethyl butyrate (AN-9) releases formaldehyde as well as butyric acid and has been used as a histone deacetylase inhibitor (21 -23). The combination of daunorubicin with pivaloyloxymethyl butyrate is synergistic in various cell lines and mouse models of leukemia (24,25). Although initially thought to be due to an interaction of the butyric acid with the anthracycline, the synergistic interaction with doxorubicin has been subsequently found to be primarily due to formaldehyde release, which results in efficient DNA adduct formation (26).…”

Section: Introductionmentioning

confidence: 99%

Activation of clinically used anthracyclines by the formaldehyde-releasing prodrug pivaloyloxymethyl butyrate

Cutts

Swift²,

Pillay³

et al. 2007

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The anthracycline group of compounds is extensively used in current cancer chemotherapy regimens and is classified as topoisomerase II inhibitor. However, previous work has shown that doxorubicin can be activated to form DNA adducts in the presence of formaldehyde-releasing prodrugs and that this leads to apoptosis independently of topoisomerase II -mediated damage. To determine which anthracyclines would be useful in combination with formaldehyde-releasing prodrugs, a series of clinically relevant anthracyclines (doxorubicin, daunorubicin, idarubicin, and epirubicin) were examined for their capacity to form DNA adducts in MCF7 and MCF7/Dx (P-glycoprotein overexpressing) cells in the presence of the formaldehydereleasing drug pivaloyloxymethyl butyrate (AN-9). All anthracyclines, with the exception of epirubicin, efficiently yielded adducts in both sensitive and resistant cell lines, and levels of adducts were similar in mitochondrial and nuclear genomes. Idarubicin was the most active compound in both sensitive and resistant cell lines, whereas adducts formed by doxorubicin and daunorubicin were consistently lower in the resistant compared with sensitive cells. The adducts formed by doxorubicin, daunorubicin, and idarubicin showed the same DNA sequence specificity in sensitive and resistant cells as assessed by L-exonuclease -based sequencing of A-satellite DNA extracted from drug-treated cells. Growth inhibition assays were used to show that doxorubicin, daunorubicin, and idarubicin were all synergistic in combination with AN-9, whereas the combination of epirubicin with AN-9 was additive. Although apoptosis assays indicated a greater than additive effect for epirubicin/AN-9 combinations, this effect was much more pronounced for doxorubicin/AN-9 combinations.

show abstract

Section: Introductionmentioning

confidence: 99%

Activation of clinically used anthracyclines by the formaldehyde-releasing prodrug pivaloyloxymethyl butyrate

Cutts

Swift²,

Pillay³

et al. 2007

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Formaldehyde reacts with doxorubicin and induces doxorubicin-DNA adduct formation and a synergistic cytotoxic response in tumor cells in culture (20,23). A combination of daunomycin (an anthracycline that is structurally similar to doxorubicin) and AN-9 was shown to increase the survival of mice inoculated with mouse monocytic leukemic cells (24). AN-9 was initially synthesized as a butyric acidreleasing prodrug to function as a histone deacetylase inhibitor (25).…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin-DNA Adducts Induce a Non-Topoisomerase II–Mediated Form of Cell Death

Swift

Rephaeli²,

Nudelman³

et al. 2006

Cancer Research

269

203

View full text Add to dashboard Cite

Doxorubicin (Adriamycin) is one of the most commonly used chemotherapeutic drugs and exhibits a wide spectrum of activity against solid tumors, lymphomas, and leukemias. Doxorubicin is classified as a topoisomerase II poison, although other mechanisms of action have been characterized. Here, we show that doxorubicin-DNA adducts ( formed by the coadministration of doxorubicin with non-toxic doses of formaldehyde-releasing prodrugs) induce a more cytotoxic response in HL-60 cells than doxorubicin as a single agent. Doxorubicin-DNA adducts seem to be independent of classic topoisomerase II-mediated cellular responses (as observed by employing topoisomerase II catalytic inhibitors and HL-60/ MX2 cells). Apoptosis induced by doxorubicin-DNA adducts initiates a caspase cascade that can be blocked by overexpressed Bcl-2, suggesting that adducts induce a classic mode of apoptosis. A reduction in the level of topoisomerase IImediated double-strand-breaks was also observed with increasing levels of doxorubicin-DNA adducts and increased levels of apoptosis, further confirming that adducts exhibit a separate mechanism of action compared with the classic topoisomerase II poison mode of cell death by doxorubicin alone. Collectively, these results indicate that the presence of formaldehyde transfers doxorubicin from topoisomerase IImediated cellular damage to the formation of doxorubicin-DNA adducts, and that these adducts are more cytotoxic than topoisomerase II-mediated lesions. These results also show that doxorubicin can induce apoptosis by a non-topoisomerase II-dependent mechanism, and this provides exciting new prospects for enhancing the clinical use of this agent and for the development of new derivatives and new tumor-targeted therapies. (Cancer Res 2006; 66(9): 4863-71)

show abstract

“…18 Earlier studies in mouse tumor models have demonstrated that AN-9 is an effective antitumor agent and displays low toxicity. 19 Currently, AN-9 is being studied in a phase II clinical trial for non-small cell lung cancer. To date, all in vitro and in vivo studies of AN-9 have been confined to solid tumors, with the exception of a murine monocytic leukemia and the HL60 cell line.…”

Section: Introductionmentioning

confidence: 99%

The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines

Batova

Shao

Diccianni

et al. 2002

Blood

View full text Add to dashboard Cite

The novel prodrug of butyric acid, pivaloyloxymethyl butyrate (AN-9), a histone deacetylase inhibitor, shows great promise as an effective and relatively nontoxic anticancer agent for solid malignancies. However, little is known about its effects on hematopoietic malignancies. In this study, we show that 21 primary samples of acute leukemia were sensitive to the antiproliferative effects of AN-9, with a 50% inhibitory concentration (IC 50 ) of 45.8 ؎ 4.1 M. In colony-forming assays, primary T-cell acute lymphoblastic leukemia (T-ALL) cells were 3-fold more sensitive to AN-9 than the normal hematopoietic progenitors, erythroid burst-forming units and granulocyte/monocyte colonyforming units. AN-9 induced apoptosis in the T-ALL cell line CEM. A common problem with cancer is chemoresistance, which is often typical of relapsed cancers. Remarkably, a T-ALL sample at diagnosis and an acute myeloid leukemia sample at relapse that were resistant to doxorubicin in vitro were sensitive to AN-9, with an IC 50

show abstract

An anti-cancer derivative of butyric acid (pivalyloxmethyl buterate) and daunorubicin cooperatively prolong survival of mice inoculated with monocytic leukaemia cells

Cited by 35 publications

References 17 publications

Activation of clinically used anthracyclines by the formaldehyde-releasing prodrug pivaloyloxymethyl butyrate

Activation of clinically used anthracyclines by the formaldehyde-releasing prodrug pivaloyloxymethyl butyrate

Doxorubicin-DNA Adducts Induce a Non-Topoisomerase II–Mediated Form of Cell Death

The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines

Contact Info

Product

Resources

About