Bcl-2 family proteins and cytoskeleton changes involved in DM-1 cytotoxic effect on melanoma cells

Faião-Flores, Fernanda; Suárez, José Agustín Quincoces; Soto‐Cerrato, Vanessa; Espona-Fiedler, Margarita; Pérez-Tomás, Ricardo; Maria, Durvanei Augusto

doi:10.1007/s13277-013-0666-6

Cited by 18 publications

(10 citation statements)

References 49 publications

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“…Cells were plated and allowed to attach overnight. After the specific treatments for each experiment, proteins were extracted and blotted as described previously (24). Total and phosphoproteins were analyzed ( Supplementary Table S1) and then the membranes were stripped and reprobed for GAPDH/vinculin/ b-actin.…”

Section: Immunoblottingmentioning

confidence: 99%

HDAC Inhibition Enhances the In Vivo Efficacy of MEK Inhibitor Therapy in Uveal Melanoma

Faião-Flores

Emmons

Durante

et al. 2019

Clinical Cancer Research

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Purpose: The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. This study has used multiomics approaches and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance. Experimental Design: Mass spectrometry-based proteomics and RNA-Seq were used to identify the signaling pathways involved in the escape of uveal melanoma cells from MEK inhibitor therapy. Mechanistic studies were performed to evaluate the escape pathways identified, and the efficacy of the MEK-HDAC inhibitor combination was demonstrated in multiple in vivo models of uveal melanoma. Results: We identified a number of putative escape pathways that were upregulated following MEK inhibition, including the PI3K/AKT pathway, ROR1/2, and IGF-1R signaling. MEK inhibition was also associated with increased GPCR expression, particularly the endothelin B receptor, and this contributed to therapeutic escape through ET-3-mediated YAP signaling. A screen of 289 clinical grade compounds identified HDAC inhibitors as potential candidates that suppressed the adaptive YAP and AKT signaling that followed MEK inhibition. In vivo, the MEK-HDAC inhibitor combination outperformed either agent alone, leading to a long-term decrease of tumor growth in both subcutaneous and liver metastasis models and the suppression of adaptive PI3K/AKT and YAP signaling. Conclusions: Together, our studies have identified GPCRmediated YAP activation and RTK-driven AKT signaling as key pathways involved in the escape of uveal melanoma cells from MEK inhibition. We further demonstrate that HDAC inhibition is a promising combination partner for MEK inhibitors in advanced uveal melanoma.

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Section: Immunoblottingmentioning

confidence: 99%

HDAC Inhibition Enhances the In Vivo Efficacy of MEK Inhibitor Therapy in Uveal Melanoma

Faião-Flores

Emmons

Durante

et al. 2019

Clinical Cancer Research

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“…The DM-1 compound (Sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3- oxo-penta-1,4-dienyl]-2-methoxy-phenolate) (Fig. 5B) is a curcumin analog that possesses curcumin’s anti-proliferative, anti-tumor, and anti-metastatic characteristics [215]. A recent study by Zhang et al [216] demonstrated that EF24 (diphenyl difluoroketone) (Fig.…”

Section: Phytochemicals For the Prevention/treatment Of Melanomamentioning

confidence: 99%

Phytochemicals for the Management of Melanoma

Pal¹,

Hunt²,

Diamond³

et al. 2016

MRMC

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Melanoma claims approximately 80% of skin cancer-related deaths. Its life-threatening nature is primarily due to a propensity to metastasize. The prognosis for melanoma patients with distal metastasis is bleak, with median survival of six months even with the latest available treatments. The most commonly mutated oncogenes in melanoma are BRAF and NRAS accounting approximately 60% and 20% of cases, respectively. In malignant melanoma, accumulating evidence suggests that multiple signaling pathways are constitutively activated and play an important role in cell proliferation, cell survival, epithelial to mesenchymal transition, metastasis and resistance to therapeutic regimens. Phytochemicals are gaining considerable attention because of their low toxicity, low cost, and public acceptance as dietary supplements. Cell culture and animals studies have elucidated several cellular and molecular mechanisms by which phytochemicals act in the prevention and treatment of metastatic melanoma. Several promising phytochemicals, such as, fisetin, epigallocatechin-3-gallate, resveratrol, curcumin, proanthocyanidins, silymarin, apigenin, capsaicin, genistein, indole-3-carbinol, and luteolin are gaining considerable attention and found in a variety of fresh fruits, vegetables, roots, and herbs. In this review, we will discuss the preventive potential, therapeutic effects, bioavailability and structure activity relationship of these selected phytochemicals for the management of melanoma.

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“…Furthermore, melanoma tumors treated with DM-1 showed a decreased Bcl-2/Bax ratio. In vitro , DM-1 also induced apoptosis via the extrinsic pathway by TNF-R1 and cleaved caspase-8 increase and by the intrinsic pathway via Bcl-2/Bax ratio decrease, cytochrome-c release and the electric mitochondrial membrane potential decrease in melanoma cells [ 9 , 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…DM-1 is a curcumin analog which has been previously studied in animal models of melanoma and breast adenocarcinoma [ 7 , 8 ]. This compound is a powerful anticancer agent with anti-proliferative and anti-metastatic activities, with minimal side effects on normal tissue due to its high selectivity for tumor cells without any significant cytotoxic effect on normal cells [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Curcumin Analog DM-1 in Monotherapy or Combinatory Treatment with Dacarbazine as a Strategy to Inhibit In Vivo Melanoma Progression

et al. 2015

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Malignant melanoma is a highly aggressive form of skin cancer with a high mortality rate if not discovered in early stages. Although a limited number of treatment options for melanoma currently exist, patients with a more aggressive form of this cancer frequently decline treatment. DM-1 is a sodium phenolate and curcumin analog with proven anticancer, anti-proliferative and anti-metastatic properties. In this paper, the DM-1 compound showed in vivo antitumor activity alone or in combination with chemotherapeutic DTIC in B16F10 melanoma-bearing mice. Beneficial effects such as melanoma tumor burden reduction with pyknotic nuclei, decreased nuclei/cytoplasmic ratio and nuclear degradation occurred after DM-1 treatment. No toxicological changes were observed in the liver, kidneys, spleen and lungs after DM-1 monotherapy or DTIC combined therapy. DTIC+DM-1 treatment induced the recovery of anemia arising from melanoma and immunomodulation. Both DM-1 treatment alone and in combination with DTIC induced apoptosis with the cleavage of caspase-3, -8 and -9. Furthermore, melanoma tumors treated with DM-1 showed a preferential apoptotic intrinsic pathway by decreasing Bcl-2/Bax ratio. Considering the chemoresistance exhibited by melanoma towards conventional chemotherapy drugs, DM-1 compound in monotherapy or in combination therapy provides a promising improvement in melanoma treatment with a reduction of side effects.

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Bcl-2 family proteins and cytoskeleton changes involved in DM-1 cytotoxic effect on melanoma cells

Cited by 18 publications

References 49 publications

HDAC Inhibition Enhances the In Vivo Efficacy of MEK Inhibitor Therapy in Uveal Melanoma

HDAC Inhibition Enhances the In Vivo Efficacy of MEK Inhibitor Therapy in Uveal Melanoma

Phytochemicals for the Management of Melanoma

Curcumin Analog DM-1 in Monotherapy or Combinatory Treatment with Dacarbazine as a Strategy to Inhibit In Vivo Melanoma Progression

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