Intrinsic Anticancer Drug Resistance of Malignant Melanoma Cells Is Abrogated by IFN-β and Valproic Acid

Roos, Wynand P.; Jöst, Eva; Belohlavek, Christina; Nagel, Georg; Fritz, Gerhard; Kaina, Bernd

doi:10.1158/0008-5472.can-10-3498

Cited by 32 publications

(27 citation statements)

References 48 publications

(71 reference statements)

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“…Examples of why metastatic melanomas are resistant to therapy are: they bypass cell-cycle checkpoints (43), they express low levels of critical apoptosis proteins (27,44), they retain p53 wild-type status (45) allowing them to upregulate DNA repair genes (DDB2, XPC; ref. 29), and they express an oncogenic form of BRAF giving them a growth advantage (46).…”

Section: Discussionmentioning

confidence: 99%

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Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance

et al. 2016

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DNA-damaging anticancer drugs remain a part of metastatic melanoma therapy. Epigenetic reprogramming caused by increased histone deacetylase (HDAC) activity arising during tumor formation may contribute to resistance of melanomas to the alkylating drugs temozolomide, dacarbazine, and fotemustine. Here, we report on the impact of class I HDACs on the response of malignant melanoma cells treated with alkylating agents. The data show that malignant melanomas in situ contain a high level of HDAC1/2 and malignant melanoma cells overexpress HDAC1/2/3 compared with noncancer cells. Furthermore, pharmacologic inhibition of class I HDACs sensitizes malignant melanoma cells to apoptosis following exposure to alkylating agents, while not affecting primary melanocytes. Inhibition of HDAC1/2/3 caused sensitization of melanoma cells to temozolomide in vitro and in melanoma xenografts in vivo. HDAC1/2/3 inhibition resulted in suppression of DNA double-strand break (DSB) repair by homologous recombination because of downregulation of RAD51 and FANCD2. This sensitized cells to the cytotoxic DNA lesion O 6 -methylguanine and caused a synthetic lethal interaction with the PARP-1 inhibitor olaparib. Furthermore, knockdown experiments identified HDAC2 as being responsible for the regulation of RAD51. The influence of class I HDACs on DSB repair by homologous recombination and the possible clinical implication on malignant melanoma therapy with temozolomide and other alkylating drugs suggests a combination approach where class I HDAC inhibitors such as valproic acid or MS-275 (entinostat) appear to counteract HDAC-and RAD51/FANCD2-mediated melanoma cell resistance. Cancer Res; 76(10); 3067-77. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

“…27) and Annexin V-FITC/propidium iodide (PI) doublestained cells have been described previously (7). Flow cytometry was performed using FACSCanto II (BD Biosciences) and the data were analyzed with WinMDI (sub-G 1 , Annexin V/PI) or ModFit (cell cycle).…”

Section: Determination Of Apoptosis and Cell Cyclementioning

confidence: 99%

Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance

et al. 2016

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“…HDAC inhibitors have been previously shown to decrease tumor growth in immunodeficient mice [33]. Valproic acid, in combination with interferon-E (IFN-E), sensitized melanoma cells to the methylating agent, temozolomide, by inducing expression of the otherwise silenced proapoptotic molecule, procaspase-8 [43]. In patients with advanced melanoma, however, valproic acid treatment did not appreciably enhance anti-tumor activity but did increase side effects when used in combination with dacarbazine and IFN-D compared to the chemoimmunotherapeutics alone [35].…”

Section: Discussionmentioning

confidence: 99%

Antitumor effect of pharmacologic ascorbate in the B16 murine melanoma model

Serrano

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et al. 2015

Free Radical Biology and Medicine

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“…VPA sensitizes melanoma cells to TMZ in vitro and in vivo by activating the apoptotic cascade. This effect is significantly increased by INF-β (Roos et al, 2011). Fourth, VPA increases the bioavailability of TMZ by reducing the clearance of the metabolite that methylates DNA (www.temodar.com).…”

Section: Unknown Mechanismsmentioning

confidence: 99%

The strategy for enhancing temozolomide against malignant glioma

Nakada¹,

Furuta²,

Hayashi³

et al. 2012

Front. Oncol.

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A combined therapy of the alkylating agent temozolomide (TMZ) and radiotherapy is standard treatment, and it improves the survival of patients with newly diagnosed glioblastoma (GBM). The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) removes the most cytotoxic lesions generated by TMZ, O6-methylguanine, establishing MGMT as one of the most important DNA repair mechanisms of TMZ-induced DNA damage. Thus, the expression of MGMT, its activity, and its promoter methylation status are associated with the response of GBM to TMZ, confirming that MGMT promotes clinical resistance to TMZ. Previous studies have shown that a variety of drugs such as interferon-β (IFN-β), levetiracetam (LEV), resveratrol, and valproic acid (VAP) increased the sensitivity of TMZ through MGMT-dependent or MGMT-independent mechanisms. In this review, we describe drugs and promising molecules that influence the responsiveness of GBM to TMZ and discuss their putative mechanism of action. In MGMT-positive GBMs, drugs that modulate MGMT activity could enhance the therapeutic activity of TMZ. Thus, administration of these drugs as an adjunct to TMZ chemotherapy may have clinical applications in patients with malignant gliomas to improve the outcome.

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Intrinsic Anticancer Drug Resistance of Malignant Melanoma Cells Is Abrogated by IFN-β and Valproic Acid

Abstract: Malignant melanoma, once metastasized, has a dismal prognosis because of intrinsic resistance to anticancer drugs. First-line therapy includes the methylating agents dacarbazine and temozolomide. Although DNA mismatch repair and O

Cited by 32 publications

References 48 publications

Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance

Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance

Antitumor effect of pharmacologic ascorbate in the B16 murine melanoma model

The strategy for enhancing temozolomide against malignant glioma

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