Anticancer Derivative of Butyric Acid (Pivalyloxymethyl Butyrate) Specifically Potentiates the Cytotoxicity of Doxorubicin and Daunorubicin through the Suppression of Microsomal Glycosidic Activity

Niitsu, Nozomi; Kasukabe, Takashi; Yokoyama, Akihiro; Okabe‐Kado, Junko; Yamamoto‐Yamaguchi, Yuri; Umeda, Masanori; Honma, Yoshio

doi:10.1124/mol.58.1.27

Cited by 28 publications

(32 citation statements)

References 32 publications

(38 reference statements)

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“…We suggest that histone hyperacetylation, by inducing a more open structure of chromatin, may promote a better binding of the drug to the relaxed chromatin DNA, thus the same amount of nuclear doxorubicin, as resulted in our experiments on doxorubicin uptake, would have an increased effect. Our results are in agreement with a report by Niitsu et al (2000) that AN 9, a derivative of butyric acid, potentiates the cytotoxicity of doxorubicin, without affecting either intracellular or nuclear uptake of the drug.…”

Section: Discussionsupporting

confidence: 83%

“…The better binding of topoisomerase II to the relaxed chromatin DNA might explain the strongly enhanced cell population in the G 2 /M phase, a situation that is closely linked to the observed induction of apoptosis. The same phenomenon has been reported in lung carcinoma cells treated with doxorubicin and AN 9 (Niitsu et al 2000). The ability of HDAC inhibitors to modulate topoisomerase II levels has been suggested as an additional mechanism for drug enhancement.…”

Section: Discussionsupporting

confidence: 56%

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Valproic acid, a histone deacetylase inhibitor, enhances sensitivity to doxorubicin in anaplastic thyroid cancer cells

Catalano¹,

Fortunati²,

Pugliese³

et al. 2006

Journal of Endocrinology

111

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Multimodality treatments (i.e. surgery, chemotherapy, and radiotherapy) are recommended for anaplastic thyroid carcinoma (ATC), an extremely lethal human cancer, but to date there is little evidence that such approaches improve survival rates. It is thus necessary to seek new therapeutic tools. Histone deacetylase (HDAC) inhibitors are a promising class of antineoplastic agents that induce differentiation and apoptosis. Moreover, they may enhance the cytotoxicity of drugs targeting DNA through acetylation of histones. Using two ATC cell lines (CAL-62 and ARO), we show here that valproic acid (VPA), a clinically available HDAC inhibitor, enhances the activity of doxorubicin, whose anti-tumor properties involve binding to DNA and inhibiting topoisomerase II. A meager 0 . 7 mM VPA, which corresponds to serum concentrations in patients treated for epilepsy, is able to increase the cytotoxicity of doxorubicin about threefold in CAL-62 cells and twofold in ARO cells. The sensitizing effect, which is through histone acetylation, involves increased apoptosis, which is also shown by the increased caspase 3 activation and the enhancement of doxorubicin-induced G 2 cell cycle arrest. These results might offer a rationale for clinical studies of a new combined therapy in an effort to improve the outcome of patients with anaplastic thyroid cancer.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 56%

Valproic acid, a histone deacetylase inhibitor, enhances sensitivity to doxorubicin in anaplastic thyroid cancer cells

Catalano¹,

Fortunati²,

Pugliese³

et al. 2006

Journal of Endocrinology

111

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“…The development of an enzyme-directed gene therapy (GDEPT) approach targeted toward specific reductase enzyme for antitumour drug bioactivation is also in progress in many laboratories (Cowen et al, 2003). However, literature data reported for some tumour cells overexpressing CPR showed the lack of enhanced sensitivity of these cells to the cytotoxicity of DOX (Schmalix et al, 1996;Ramji et al, 2003), whereas a study by Niitsu et al (2000) reported that decrease in intracellular CPR level increased DOX cytotoxicity. It suggests that the reductive activation of DOX in situ in target cells by CPR could be influenced by several cellular factors, for example, bioavailability of NADPH, competitive metabolic pathways of the drug catalysed by other enzymes depending on their cellular levels or rapid decomposition of ROS and DOX free radicals by the antioxidant defence system of the cell.…”

Section: Discussionmentioning

confidence: 97%

“…Additionally, because it is proposed that CPR could also play an important role in the detoxication pathway via the reductive deglycosylation of DOX, some studies were focused on studying the cytotoxic activity against tumour cells presenting decreased CPR expression. It was shown that the suppression of CPR activity in human non-small cell lung carcinoma EBC-1 and PC9 and BALM3 lymphoma cell lines realized via pharmacological methods as well as the antisense approach resulted in increasing cytotoxic activity of DOX (Niitsu et al, 2000).…”

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confidence: 99%

The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

et al. 2005

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Clinical usefulness of doxorubicin (DOX) is limited by the occurrence of multidrug resistance (MDR) associated with the presence of membrane transporters (e.g. P-glycoprotein, MRP1) responsible for the active efflux of drugs out of resistant cells. Doxorubicin is a well-known bioreductive antitumour drug. Its ability to undergo a one-electron reduction by cellular oxidoreductases is related to the formation of an unstable semiquionone radical and followed by the production of reactive oxygen species. There is an increasing body of evidence that the activation of bioreductive drugs could result in the alkylation or crosslinking binding of DNA and lead to the significant increase in the cytotoxic activity against tumour cells. The aim of this study was to examine the role of reductive activation of DOX by the human liver NADPH cytochrome P450 reductase (CPR) in increasing its cytotoxic activity especially in regard to MDR tumour cells. It has been evidenced that, upon CPR catalysis, DOX underwent only the redox cycling (at low NADPH concentration) or a multistage chemical transformation (at high NADPH concentration). It was also found, using superoxide dismutase (SOD), that the first stage undergoing reductive activation according to the mechanism of the redox cycling had the key importance for the metabolic conversion of DOX. In the second part of this work, the ability of DOX to inhibit the growth of human promyelocytic-sensitive leukaemia HL60 cell line as well as its MDR sublines exhibiting two different phenotypes of MDR related to the overexpression of P-glycoprotein (HL60/VINC) or MRP1 (HL60/DOX) was studied in the presence of exogenously added CPR. Our assays showed that the presence of CPR catalysing only the redox cycling of DOX had no effect in increasing its cytotoxicity against sensitive and MDR tumour cells. In contrast, an important increase in cytotoxic activity of DOX after its reductive conversion by CPR was observed against HL60 as well as HL60/VINC and HL60/DOX cells.

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“…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

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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.

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Anticancer Derivative of Butyric Acid (Pivalyloxymethyl Butyrate) Specifically Potentiates the Cytotoxicity of Doxorubicin and Daunorubicin through the Suppression of Microsomal Glycosidic Activity

Cited by 28 publications

References 32 publications

Valproic acid, a histone deacetylase inhibitor, enhances sensitivity to doxorubicin in anaplastic thyroid cancer cells

Valproic acid, a histone deacetylase inhibitor, enhances sensitivity to doxorubicin in anaplastic thyroid cancer cells

The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

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

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