Everolimus selectively targets vemurafenib resistant BRAFV600E melanoma cells adapted to low pH

Ruzzolini, Jessica; Peppicelli, Silvia; Andreucci, Elena; Bianchini, Francesca; Margheri, Francesca; Laurenzana, Anna; Fibbi, Gabriella; Pimpinelli, Nicola; Calorini, Lido

doi:10.1016/j.canlet.2017.08.010

Cited by 38 publications

(64 citation statements)

References 36 publications

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“…The highest reductions in the activity of metalloproteinases and the invasiveness of melanoma cells were obtained with the combination of the B-RAF inhibitor-PLX-4032 and mTOR inhibitor-everolimus. Similar observations were reported for A375M6 melanoma cell line [22].…”

Section: Protein Kinase Inhibitors and Melanoma Cell Invasionsupporting

confidence: 90%

mTOR inhibitor everolimus reduces invasiveness of melanoma cells

et al. 2019

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The mammalian target of rapamycin (mTOR) plays a key role in several cellular processes: proliferation, survival, invasion, and angiogenesis, and therefore, controls cell behavior both in health and in disease. Dysregulation of the mTOR signaling is involved in some of the cancer hallmarks, and thus the mTOR pathway is an important target for the development of a new anticancer therapy. The object of this study is recognition of the possible role of mTOR kinase inhibitors-everolimus single and in combination with selected downstream protein kinases inhibitors: LY294002 (PI3 K), U0126 (ERK1/2), GDC-0879 (B-RAF), AS-703026 (MEK), MK-2206 (AKT), PLX-4032 (B-RRAF) in cell invasion in malignant melanoma. Treatment of melanoma cells with everolimus led to a significant decrease in the level of both phosphorylated: mTOR (Ser2448) and mTOR (Ser2481) as well as their downstream effectors. The use of protein kinase inhibitors produced a significant decrease in metalloproteinases (MMPs) activity, as well as diminished invasion, especially when used in combination. The best results in the inhibition of both MMPs and cell invasiveness were obtained for the combination of an mTOR inhibitor-everolimus with a B-RAF inhibitor-PLX-4032. Slightly less profound reduction of invasiveness was obtained for the combinations of an mTOR inhibitor-everolimus with ERK1/2 inhibitor-U126 or MEK inhibitor-AS-703026 and in the case of MMPs activity decrease for PI3 K inhibitor-LY294002 and AKT inhibitor-MK-2206. The simultaneous use of everolimus or another new generation rapalog with selected inhibitors of crucial signaling kinases seems to be a promising concept in cancer treatment.

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Section: Protein Kinase Inhibitors and Melanoma Cell Invasionsupporting

confidence: 90%

mTOR inhibitor everolimus reduces invasiveness of melanoma cells

et al. 2019

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“…Lactate may contribute to sustain proliferation either by stimulating the production of vascular endothelial growth factor or by promoting cellular motility, two favorable aspects for proliferating cancer cells, e.g., generation of new blood vessels and expansion in neighboring tissues [3]. Lactic acid production and its release into the tumor microenvironment helps reduce the local extracellular pH, which might be instrumental for tumor progression, by promoting the invasive abilities of cancer cells [4], their resistance to apoptotic stimuli as well as chemo-and target therapies [5], by inducing anoikis resistance thus favouring tumor cell survival into the circulatory system [6], and importantly, by inhibiting the immune response supporting tumor cell escape [7]. The Warburg phenotype is regulated by numerous oncogenes, e.g., MYC transcription factor has been found to activate lactate dehydrogenase (LDH)A [8], and promote the switch from pyruvate kinase muscle isozyme 1 (PKM1) to 2 (PKM2), a limiting glycolytic enzyme of the final step of glycolysis, involved in the pyruvate and ATP production from phosphoenolpyruvate [9].…”

Section: Introductionmentioning

confidence: 99%

Cancer Glycolytic Dependence as a New Target of Olive Leaf Extract

Ruzzolini

Peppicelli

Bianchini

et al. 2020

Cancers

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Oleuropein (Ole), the main bioactive phenolic component of Olea europaea L. has recently attracted the scientific attention for its several beneficial properties, including its anticancer effects. This study is intended to investigate whether an olive leaf extract enriched in Ole (OLEO) may counteract the aerobic glycolysis exploited by tumor cells. We found that OLEO decreased melanoma cell proliferation and motility. OLEO was also able to reduce the rate of glycolysis of human melanoma cells without affecting oxidative phosphorylation. This reduction was associated with a significant decrease of glucose transporter-1, protein kinase isoform M2 and monocarboxylate transporter-4 expression, possible drivers of such glycolysis inhibition. Extending the study to other tumor histotypes, we observed that the metabolic effects of OLEO are not confined to melanoma, but also confirmed in colon carcinoma, breast cancer and chronic myeloid leukemia. In conclusion, OLEO represents a natural product effective in reducing the glycolytic metabolism of different tumor types, revealing an extended metabolic inhibitory activity that may be well suited in a complementary anti-cancer therapy.

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“…Activation of PI3K/AKT/mTOR pathway represents one of the major mechanisms of acquired resistance to both targeted BRAF inhibitors and DTIC [38,39]. We have found that BRAF melanoma cells exposed to a low extracellular pH medium acquired a resistance to both BRAF and MEK inhibitors but were still sensitive to the inhibition of AKT/mTOR pathway induced by RAD001 [33].…”

Section: Discussionmentioning

confidence: 89%

“…mTOR inhibiting agents, including RAD001, are effective in inhibiting the PI3K/AKT/mTOR pathway, although several reports indicate that mTOR inhibitors have limited single-agent activity against melanoma [32]. Further, our recent research effort demonstrates that RAD001 might overcome PLX4032 resistance acquired by melanoma cells grown under a low extracellular pH [33]. These indications prompted us to study a possible cooperation between Ole and RAD001 and we found that Ole is a potent promoter of RAD001 cytotoxicity (Fig.…”

Section: Combination Of Ole With Everolimus (Rad001)mentioning

confidence: 92%

Oleuropein, the Main Polyphenol of <em>Olea europaea </em>Leaf Extract, Has an Anti Cancer Effect on Human BRAF Melanoma Cells and Potentiates the Cytotoxicity of Current Chemotherapies

Ruzzolini¹,

Peppicelli²,

Andreucci³

et al. 2018

Preprint

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Oleuropein (Ole), a secoiridoid glucoside present in Olea europaea leaves, gained the interest of many scientists thanks to its several biological properties, including the anticancer one. We verified whether Ole might potentiate cytotoxicity of conventional drugs used to treat melanoma, disclosing new potential therapeutic strategy. We tested the cytotoxic action of Ole alone or in combination with chemotherapeutics on A375 human melanoma cells. We found that Ole was able, at a dose of 500 μM, to stimulate apoptosis in melanoma cells, while at a non-toxic dose of 250 μM, it affected cell proliferation and induced the downregulation of pAKT/pS6 pathway. 250 μM Ole did not potentiate the effect of Vemurafenib (PLX4032), but it succeeded in increase the cytotoxic effect of Dacarbazine (DTIC). The mayor effect was found in the association between Ole and Everolimus (RAD001), also on PLX4032-resistant BRAF melanoma cells, possibly cooperating in the inhibition of pAKT/pS6 pathway. Of interest, an olive leaf extract enriched in equimolar Ole was more effective and able to further improve DTIC and, particularly, RAD001 efficacy on BRAF melanoma cells than Ole alone. Therefore, Ole represents a natural product able to potentiate a wide array of chemotherapeutics against BRAF melanoma cells affecting pAKT/pS6 pathway.

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Everolimus selectively targets vemurafenib resistant BRAFV600E melanoma cells adapted to low pH

Cited by 38 publications

References 36 publications

mTOR inhibitor everolimus reduces invasiveness of melanoma cells

mTOR inhibitor everolimus reduces invasiveness of melanoma cells

Cancer Glycolytic Dependence as a New Target of Olive Leaf Extract

Oleuropein, the Main Polyphenol of <em>Olea europaea </em>Leaf Extract, Has an Anti Cancer Effect on Human BRAF Melanoma Cells and Potentiates the Cytotoxicity of Current Chemotherapies

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