Evidence map›Paper›PMID 26487273›Full record

ArticleLeukemia2016

Halting pro-survival autophagy by TGFβ inhibition in bone marrow fibroblasts overcomes bortezomib resistance in multiple myeloma patients.

M A Frassanito, K De Veirman, V Desantis, L Di Marzo, D Vergara, S Ruggieri, T Annese, B Nico, E Menu, I Catacchio and 10 more

Abstract read
PubMed Publisher
In one paragraph

Article in Leukemia, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.

0numbers the graph read from it
0cells of the map it votes in
53citing papers in PubMed
4.8field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

53 citing papers in PubMed, 81 citations in OpenAlex.

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  16. Autophagy-related mechanisms for treatment of multiple myeloma.Cancer drug resistance (Alhambra, Calif.) · 2023
    Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors at 3 institutions in 2 countries.

M A FrassanitoDepartment of Biomedical Sciences and Human Oncology, General Pathology Unit, University of Bari Medical School, Bari, Italy.
K De VeirmanDepartment of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
V DesantisDepartment of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
L Di MarzoDepartment of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
D VergaraDepartment of Biological and Environmental Sciences and Technologies, University of Salento, Laboratory of Clinical Proteomics, "Giovanni Paolo II" Hospital, ASL-Lecce, Italy.
S RuggieriDepartment of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Medical School, Bari, Italy.
T AnneseDepartment of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Medical School, Bari, Italy.
B NicoDepartment of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Medical School, Bari, Italy.ORCID http://orcid.org/0000-0003-4768-8431
E MenuDepartment of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
I CatacchioDepartment of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
R RiaDepartment of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
V RacanelliDepartment of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
M MaffiaDepartment of Biological and Environmental Sciences and Technologies, University of Salento, Laboratory of Clinical Proteomics, "Giovanni Paolo II" Hospital, ASL-Lecce, Italy.
E AngelucciDepartment of Haematology, Businco Hospital, Cagliari, Italy.
D DerudasDepartment of Haematology, Businco Hospital, Cagliari, Italy.
R FumaruloDepartment of Biomedical Sciences and Human Oncology, General Pathology Unit, University of Bari Medical School, Bari, Italy.
F DammaccoDepartment of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
D RibattiDepartment of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Medical School, Bari, Italy.
K VanderkerkenDepartment of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
A VaccaDepartment of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
University of Bari Aldo Moro · ITVrije Universiteit Brussel · BEUniversity of Salento · IT

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Bortezomib (bort) has improved overall survival in patients with multiple myeloma (MM), but the majority of them develop drug resistance. In this study, we demonstrate that bone marrow (BM) fibroblasts (cancer-associated fibroblasts; CAFs) from bort-resistant patients are insensitive to bort and protect the RPMI8226 and patients' plasma cells against bort-induced apoptosis. Bort triggers CAFs to produce high levels of interleukin (IL)-6, IL-8, insulin-like growth factor (IGF)-1 and transforming growth factor (TGF) β. Proteomic studies on CAFs demonstrate that bort resistance parallels activation of oxidative stress and pro-survival autophagy. Indeed, bort induces reactive oxygen species in bort-resistant CAFs and activates autophagy by increasing light chain 3 protein (LC3)-II and inhibiting p62 and phospho-mammalian target of rapamycin. The small-interfering RNA knockdown of Atg7, and treatment with 3-methyladenine, restores bort sensitivity in bort-resistant CAFs and produces cytotoxicity in plasma cells co-cultured with CAFs. In the syngeneic 5T33 MM model, bort-treatment induces the expansion of LC3-II(+) CAFs. TGFβ mediates bort-induced autophagy, and its blockade by LY2109761, a selective TβRI/II inhibitor, reduces the expression of p-Smad2/3 and LC3-II and induces apoptosis in bort-resistant CAFs. A combination of bort and LY2109761 synergistically induces apoptosis of RPMI8226 co-cultured with bort-resistant CAFs. These data define a key role for CAFs in bort resistance of plasma cells and provide the basis for a novel targeted therapeutic approach.

Indexed as

Gene Expression Regulation, NeoplasticAgedAged, 80 and overAnimalsAntineoplastic AgentsAutophagyBone Marrow CellsBortezomibDrug CombinationsDrug Resistance, NeoplasmFemaleFibroblastsHumansMaleMiceMicrotubule-Associated ProteinsAntineoplastic AgentsBortezomibDrug CombinationsLY2109761MAP1LC3A protein, humanMicrotubule-Associated ProteinsMTOR protein, humanP62 protein, humanPyrazolesPyrrolesRNA-Binding ProteinsTOR Serine-Threonine KinasesTransforming Growth Factor beta

Identifiers

PMID26487273
OpenAlexW2168964154

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.