Reactive Oxygen Species–Mediated Synergism of Fenretinide and Romidepsin in Preclinical Models of T-cell Lymphoid Malignancies

Abstract

T-cell lymphoid malignancies (TCLM) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitor romidepsin and the synthetic cytotoxic retinoid fenretinide both have achieved durable clinical responses in T-cell lymphomas as single agents. We investigated the potential for using these two agents in combination in TCLMs. We demonstrated cytotoxic synergy between romidepsin and fenretinide in 15 TCLM cell lines at clinically achievable concentrations that lacked cytotoxicity for nonmalignant cells (fibroblasts and blood mononuclear cells). , romidepsin + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous and disseminated TCLM xenograft models than single-agent romidepsin or fenretinide + ketoconazole. Fenretinide + romidepsin caused a reactive oxygen species (ROS)-dependent increase in proapoptotic proteins (Bim, tBid, Bax, and Bak), apoptosis, and inhibition of HDAC enzymatic activity, which achieved a synergistic increase in histone acetylation. The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + romidepsin were abrogated by antioxidants (vitamins C or E). Romidepsin + fenretinide activated p38 and JNK via ROS, and knockdown of p38 and JNK1 significantly decreased the synergistic cytotoxicity. Romidepsin + fenretinide also showed synergistic cytotoxicity for B-lymphoid malignancy cell lines, but did not increase ROS, acetylation of histones, activation of p38 + JNK, or cytotoxicity in nonmalignant cells. Romidepsin + fenretinide achieved synergistic activity in preclinical models of TCLMs, but not in nonmalignant cells, via a novel molecular mechanism. These data support conducting clinical trials of romidepsin + fenretinide in relapsed and refractory TCLMs..

Oxidative Stress Gene Expression Profile Correlates with Cancer Patient Poor Prognosis: Identification of Crucial Pathways Might Select Novel Therapeutic Approaches

“…Ionizing radiations represent other important ROS inducers, because they are able to promote by themselves high level of ROS and also because they might increase NADPH oxidase, an important source of ROS [32]. Moreover, we and others have demonstrated, in different models and in different combination settings, that oxidative injury played a significant functional role in the antitumor effect of histone deacetylase inhibitors (HDACi), a class of epigenetic antitumor compounds currently in clinical practice in haematological malignancies [7, 13, 33–42]. …”

Cytotoxic activity of difluoromethylornithine compared with fenretinide in neuroblastoma cell lines

“…N‐(4‐hydroxyphenyl)retinamide fenretinide (4‐HPR), a synthetic retinoid, has been reported to be cytotoxic and/or inhibit the growth of neuroblastoma and other cancer cell lines . At concentrations achievable in patients, fenretinide induced multilog cytotoxicity in neuroblastoma cell lines resistant to all‐trans retinoic acid or 13‐cis‐RA .…”

“…N-(4-hydroxyphenyl)retinamide fenretinide (4-HPR), a synthetic retinoid, has been reported to be cytotoxic and/or inhibit the growth of neuroblastoma [7][8][9][10] and other cancer cell lines. [10][11][12] At concentrations achievable in patients, fenretinide induced multilog cytotoxicity in neuroblastoma cell lines resistant to all-trans retinoic acid or 13-cis-RA. 7 Fenretinide does not induce cancer cell differentiation but is cytotoxic, independent of retinoid receptor or p53 pathways through increases of reactive oxygen species [12][13][14] and dihydroceramides.…”

“…[10][11][12] At concentrations achievable in patients, fenretinide induced multilog cytotoxicity in neuroblastoma cell lines resistant to all-trans retinoic acid or 13-cis-RA. 7 Fenretinide does not induce cancer cell differentiation but is cytotoxic, independent of retinoid receptor or p53 pathways through increases of reactive oxygen species [12][13][14] and dihydroceramides. 8,11 The initial capsule formulation of fenretinide had low bioavailability (1-3 M).…”

A conserved mechanism for regulation of endo-lysosomal pH by histone deacetylases

“…Whereas lysine acetylation on histone tails interferes with generation of higher order chromatin structures and promotes access and binding of transcription factors, histone deacetylation favors chromatin packing and represses gene transcription (10)(11)(12). Histone deacetylase (HDAC) inhibitors have been approved for the treatment of hematologic cancers and are being considered as promising therapy to reverse disease-associated epigenetic states in a range of cardiovascular, neurodegenerative and inflammatory diseases (11)(12)(13)(14). Given their broad application, our findings offer potential therapeutic options to treat endo-lysosomal pH dysfunction in autism, AD, and other neurodegenerative disorders.…”