Lanreotide Induces Cytokine Modulation in Intestinal Neuroendocrine Tumors and Overcomes Resistance to Everolimus

Sciammarella, Concetta; Luce, Amalia; Riccardi, Ferdinando; Mocerino, Carmela; Modica, Roberta; Berretta, Massimiliano; Misso, Gabriella; Cossu, Alessia Maria; Colao, Annamaria; Mantovani, Giovanna; Nečas, Alois; Fedačko, Ján; Galdiero, Marilena; Correale, Pierpaolo; Faggiano, Antongiulio; Caraglia, Michele; Capasso, Anna; Grimaldi, Anna

doi:10.3389/fonc.2020.01047

Cited by 13 publications

(6 citation statements)

References 41 publications

(49 reference statements)

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“…Moreover, the present findings reveal that the chronic EVE exposure induces the inhibition of phosphorylation in Thr389 and in Ser65 in both mTOR pathway components, p70S6K and 4eBP1, respectively, and the activation of Akt in Ser473 in both JHH-6 and PLC/PRF/5 cell models. These data are in line with what has been previously reported even in the BON-1 cell line, a model of pancreatic neuroendocrine tumor, in which a long-lasting (8 weeks) exposure to EVE induced mTOR pathway inactivation of pp70S6K on Thr389 and of p4eBP1 on Thr70 ( 23 ). Remarkably, the reduction of molecular target activity is one of best-known mechanisms of resistance to target-based agents.…”

Section: Discussionsupporting

confidence: 92%

Vitamin D Reverts the Exosome-Mediated Transfer of Cancer Resistance to the mTOR Inhibitor Everolimus in Hepatocellular Carcinoma

et al. 2022

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Several multi-kinase inhibitors were widely tested as potential first-line or second-line therapy in patients with advanced hepatocellular carcinoma (HCC). However, acquired drug resistance limits their clinical efficacy. Exosomes are microvesicles secreted by tumor and stromal cells that participate in many biological processes, including drug resistance. The current study evaluated the capability of exosomes derived from everolimus (EVE)-resistant HCC cells in inducing drug resistance in parental human HCC cells and the effect of 1,25(OH)2Vitamin D (VitD) treatment in restoring EVE sensitivity. The internalization of exosomes from EVE-resistant (EveR) cells into parental cells conferred the transmission of aggressive phenotype by promoting the transition of epithelial-to-mesenchymal phenotype, as demonstrated by immunofluorescence, and the acquisition of EVE resistance, as demonstrated by cell proliferation and colony formation assays. Moreover, the internalization of exosomes from EveR into parental cells induced deregulation of the mTOR pathway mainly by triggering the activation of the serine/threonine protein kinase Akt, involved in the cellular survival pathway, as demonstrated by Western blot analysis. Interestingly, the treatment with VitD prevented exosome-induced EVE resistance in HCC cells, significantly inhibiting cell proliferation but also partially reducing colony and size number when combined with EVE compared with control. In conclusion, the results of the current study demonstrated that exosomes derived from EveR cells could induce EVE resistance in EVE-sensitive HCC cells and that VitD can revert the exosome-induced EVE resistance by resensitizing to EVE treatment.

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Section: Discussionsupporting

confidence: 92%

Vitamin D Reverts the Exosome-Mediated Transfer of Cancer Resistance to the mTOR Inhibitor Everolimus in Hepatocellular Carcinoma

et al. 2022

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“…Vitale and colleagues showed a synergy between everolimus and demethylating agent 5-aza-2 0 -deoxycytidine (AZA) in chemoradiotherapy resistant medullary thyroid cancer cells (23). We did not observe any synergy with everolimus and somatostatin analogs which is in agreement with the findings of Krug and colleagues (24), however, a study has demonstrated that lanreotide inhibited the cell growth syngergistically in everolimus-resistant BON1 cells (25). In contrast, Hue-Fontaine and colleagues did not observed synergy between everolimus and metformin in the diabetic patients (26) maybe because of the targeting of same pathway.…”

Section: Discussionsupporting

confidence: 89%

PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus

Mpilla

Uddin

Hallak

et al. 2021

Molecular Cancer Therapeutics

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Metastatic pancreatic neuroendocrine tumors (PNET) remain an unmet clinical problem. Chronologic treatment in PNETs includes observation (watchful protocol), surgery, targeted therapy, and chemotherapy. However, increasing evidence illustrates that the outcomes of targeted therapeutic options for the treatment of advanced PNETs show minimal response. The FDA-approved mTOR inhibitor everolimus does not shrink these tumors. It only delays disease progression in a subset of patients, while a significant fraction acquires resistance and shows disease progression. Thus, there is a need for more effective targeted approaches to sensitize PNETs to everolimus for better treatment outcomes. Previously, we showed that mTOR regulator p21 activated kinase 4 (PAK4) and nicotinamide adenine dinucleotide biosynthesis enzyme nicotinamide phosphoribosyl transferase (NAMPT) were aberrantly expressed in PNET tissue and promoted everolimus resistance. In this report, we demonstrate that PAK4-NAMPT dual inhibitor KPT-9274 can synergize with everolimus (growth inhibition, colony suppression, and glucose uptake assays). KPT-9274-everolimus disrupted spheroid formation in multiple PNET models. Molecular analysis showed alteration of mTORC2 through downregulation of RICTOR as a mechanism supporting synergy with everolimus in vitro. KPT-9274 suppressed β-catenin activity via inhibition of PAK4, highlighting the cross-talk between Rho GTPases and Wnt signaling in PNETs. KPT-9274, given at 150 mg/kg in combination with sub-MTD everolimus (2.5 mg/kg), significantly suppressed two PNET-derived xenografts. These studies bring forward a well-grounded strategy for advanced PNETs that fail to respond to single-agent everolimus.

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“…Additional references are cited within the Supporting Information. [25,40,47,49,50] Author Contributions AB conceived the project, optimized reactions, analyzed data and wrote the manuscript; AC performed most of the synthesis, conjugation reactions, in vitro cell assays, data analysis, and helped with manuscript preparation. SC assisted in purification, data analysis, peptide-related chemistries, and all chemical data analysis; AK and TJDK performed and documented all DFT calculations.…”

Section: Supporting Informationmentioning

confidence: 99%

Sulfonyl Diazaborine ‘Click’ Chemistry Enables Rapid and Efficient Bioorthogonal Labeling**

Chowdhury

Chatterjee

Kushwaha

et al. 2023

Chemistry A European J

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Finding an ideal bioorthogonal reaction that responds to a wide range of biological queries and applications is of great interest in biomedical applications. Rapid diazaborine (DAB) formation in water by the reactions of ortho‐carbonyl phenylboronic acid with α‐nucleophiles is an attractive conjugation module. Nevertheless, these conjugation reactions demand to satisfy stringent criteria for bioorthogonal applications. Here we show that widely used sulfonyl hydrazide (SHz) offers a stable DAB conjugate by combining with ortho‐carbonyl phenylboronic acid at physiological pH, competent for an optimal biorthogonal reaction. Remarkably, the reaction conversion is quantitative and rapid (k2>103 M−1 s−1) at low micromolar concentrations, and it preserves comparable efficacy in a complex biological milieu. DFT calculations support that SHz facilitates DAB formation via the most stable hydrazone intermediate and the lowest energy transition state compared to other biocompatible α‐nucleophiles. This conjugation is extremely efficient on living cell surfaces, enabling compelling pretargeted imaging and peptide delivery. We anticipate this work will permit addressing a wide range of cell biology queries and drug discovery platforms exploiting commercially available sulfonyl hydrazide fluorophores and derivatives.

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Lanreotide Induces Cytokine Modulation in Intestinal Neuroendocrine Tumors and Overcomes Resistance to Everolimus

Cited by 13 publications

References 41 publications

Vitamin D Reverts the Exosome-Mediated Transfer of Cancer Resistance to the mTOR Inhibitor Everolimus in Hepatocellular Carcinoma

Vitamin D Reverts the Exosome-Mediated Transfer of Cancer Resistance to the mTOR Inhibitor Everolimus in Hepatocellular Carcinoma

PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus

Sulfonyl Diazaborine ‘Click’ Chemistry Enables Rapid and Efficient Bioorthogonal Labeling**

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