Histone deacetylase inhibitors induce thymidine phosphorylase expression in cultured breast cancer cell lines

Puppin, Cinzia; Puglisi, Fabio; Pandolfi, Maura; Loreto, Carla Di; Damante, Giuseppe

doi:10.3892/or.2011.1310

Cited by 5 publications

(4 citation statements)

References 24 publications

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“…VPA up-regulates TP, both in vitro and in vivo , through a transcriptional mechanism, which confirmed the results obtained by our group in colorectal cancer models and those of Puppin et al in breast cancer cells [ 18 , 26 ].…”

Section: Discussionsupporting

confidence: 90%

“…We then demonstrated that HDACi with different specificity are able to modulate TP and TS protein levels in all breast cancer cell lines, as previously described by us and other groups in different tumor models [ 18 , 25 , 26 ]. Both pan-HDACi (e.g., vorinostat, trichostatin-A, panobinostat) and class-I/IIa (e.g., VPA) or class-I HDACi (e.g., entinostat) are able to up-regulate TP and down-regulate TS expression in MCF-7 cells.…”

Section: Resultssupporting

confidence: 78%

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Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression

et al. 2015

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The prognosis of patients with metastatic breast cancer remains poor, and thus novel therapeutic approaches are needed. Capecitabine, which is commonly used for metastatic breast cancer in different settings, is an inactive prodrug that takes advantage of elevated levels of thymidine phosphorylase (TP), a key enzyme that is required for its conversion to 5-fluororacil, in tumors. We demonstrated that histone deacetylase inhibitors (HDACi), including low anticonvulsant dosage of VPA, induced the dose- and time-dependent up-regulation of TP transcript and protein expression in breast cancer cells, but not in the non-tumorigenic breast MCF-10A cell line. Through the use of siRNA or isoform-specific HDACi, we demonstrated that HDAC3 is the main isoform whose inhibition is involved in the modulation of TP. The combined treatment with capecitabine and HDACi, including valproic acid (VPA), resulted in synergistic/additive antiproliferative and pro-apoptotic effects in breast cancer cells but not in TP-knockout cells, both in vitro and in vivo, highlighting the crucial role of TP in the synergism observed. Overall, this study suggests that the combination of HDACi (e.g., VPA) and capecitabine is an innovative antitumor strategy that warrants further clinical evaluation for the treatment of metastatic breast cancer.

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Section: Discussionsupporting

confidence: 90%

Section: Resultssupporting

confidence: 78%

Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression

et al. 2015

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“…High TP expression levels has been found in some tumor tissues like stomach, colon and ovary tumor sites [39]. The expression of TP has been confirmed in various cancer cell lines such as HT-29 [40,41], SKBR3 [42], A431 [43] and A549 [43]. On the other hand, the level of TP expression may vary from different colon cancer cell lines [44].…”

Section: Resultsmentioning

confidence: 99%

Enhanced Anticancer Activity of 5’-DFUR-PCL-MPEG Polymeric Prodrug Micelles Encapsulating Chemotherapeutic Drugs

et al. 2018

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The compound 5’-deoxy-5-fluorouridine (5’-DFUR) is a prodrug of the anti-tumor drug 5-fluorouracil (5-FU). Thymidine phosphorylase (TP) is an enzyme that can convert 5’-DFUR to its active form 5-FU and the expression of TP is upregulated in various cancer cells. In this study, 5’-DFUR associated with amphiphilic copolymer poly(ε-caprolactone)-methoxy poly(ethylene glycol) (5’-DFUR-PCL-MPEG) was synthesized, characterized, and self-assembled into functional polymeric micelles. To demonstrate that the prodrug 5’-DFUR could convert into cytotoxic 5-fluorouracil (5-FU) by endogenous TP, HT-29 colorectal cancer cells were treated with 5’-DFUR-PCL-MPEG polymeric micelles for various time periods. Chemotherapeutic drugs doxorubicin (DOX) and 7-ethyl-10-hydroxycamptothecin (SN-38) were also encapsulated separately into 5’-DFUR-PCL-MPEG polymeric micelles to create a dual drug-loaded system. HT-29 cells were treated with DOX or SN-38 encapsulated 5’-DFUR-PCL-MPEG polymeric micelles to examine the efficacy of dual drug-loaded micelles. As a result, HT-29 cells treated with 5’-DFUR-PCL-MPEG polymeric micelles showed up to 40% cell death rate after a 72-h treatment. In contrast, HT-29 cells challenged with DOX or SN-38 encapsulated 5’-DFUR-incorporated polymeric micelles showed 36% and 31% in cell viability after a 72-h treatment, respectively.

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“…We and others have previously demonstrate that HDACi, including VPA, synergize with either 5-FU or capecitabine because are able to modulate the levels of two critical enzymes in the metabolism of fluoropyrimidines such as TP and TS [ 17 , 18 , 36 – 39 ]. Notably, TP knockdown experiments confirmed a crucial role of TP protein up-regulation in the observed synergism [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Synergistic antitumor interaction between valproic acid, capecitabine and radiotherapy in colorectal cancer: critical role of p53

Terranova-Barberio

Pecori

Roca

et al. 2017

J Exp Clin Cancer Res

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BackgroundRecurrence with distant metastases has become the predominant pattern of failure in locally advanced rectal cancer (LARC), thus the integration of new antineoplastic agents into preoperative fluoropyrimidine-based chemo-radiotherapy represents a clinical challenge to implement an intensified therapeutic strategy.The present study examined the combination of the histone deacetylase inhibitor (HDACi) valproic acid (VPA) with fluoropyrimidine-based chemo-radiotherapy on colorectal cancer (CRC) cells.MethodsHCT-116 (p53-wild type), HCT-116 p53−/− (p53-null), SW620 and HT29 (p53-mutant) CRC cell lines were used to assess the antitumor interaction between VPA and capecitabine metabolite 5′-deoxy-5-fluorouridine (5′-DFUR) in combination with radiotherapy and to evaluate the role of p53 in the combination treatment. Effects on proliferation, clonogenicity and apoptosis were evaluated, along with γH2AX foci formation as an indicator for DNA damage.ResultsCombined treatment with equipotent doses of VPA and 5′-DFUR resulted in synergistic effects in CRC lines expressing p53 (wild-type or mutant). In HCT-116 p53−/− cells we observed antagonist effects. Radiotherapy further potentiated the antiproliferative, pro-apoptotic and DNA damage effects induced by 5′-DFUR/VPA combination in p53 expressing cells.ConclusionsThese results highlighted the role of VPA as valuable candidate to be added to preoperative chemo-radiotherapy in LARC. On these bases we launched the ongoing phase I/II study of VPA and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer (V-shoRT-R3).Electronic supplementary materialThe online version of this article (10.1186/s13046-017-0647-5) contains supplementary material, which is available to authorized users.

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Histone deacetylase inhibitors induce thymidine phosphorylase expression in cultured breast cancer cell lines

Cited by 5 publications

References 24 publications

Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression

Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression

Enhanced Anticancer Activity of 5’-DFUR-PCL-MPEG Polymeric Prodrug Micelles Encapsulating Chemotherapeutic Drugs

Synergistic antitumor interaction between valproic acid, capecitabine and radiotherapy in colorectal cancer: critical role of p53

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