N-benzyladriamycin-14-valerate (AD 198) exhibits potent anti-tumor activity on TRAF3-deficient mouse B lymphoma and human multiple myeloma

Edwards, Shanique; Moore, Cynthia; Liu, Yan; Grewal, Sukhdeep; Covey, Lori R.; Xie, Ping

doi:10.1186/1471-2407-13-481

Cited by 22 publications

(68 citation statements)

References 54 publications

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“…Human MM cell lines 8226 (contains bi-allelic TRAF3 deletions), KMS11 (contains bi-allelic TRAF3 deletions), and LP1 (contains inactivating TRAF3 frameshift mutations) were kindly provided by Dr. Leif Bergsagel (Mayo Clinic, Scottsdale, AZ), and were cultured as previously described [18]. TRAF3 −/− mouse B lymphoma cell lines 27-9.5.3, 105-8.1B6, and 115-6.1.2 were generated and cultured as described previously [14,18].…”

Section: Methodsmentioning

confidence: 99%

“…TRAF3 −/− mouse B lymphoma cell lines 27-9.5.3, 105-8.1B6, and 115-6.1.2 were generated and cultured as described previously [14,18]. Bortezomib was generously supplied by Millennium Pharmaceuticals (Cambridge, MA).…”

Section: Methodsmentioning

confidence: 99%

“…Rabbit polyclonal antibody against Noxa was purchased from AXXORA (Farmingdale, NY). Other antibodies and reagents used in this study were described previously [14,18–20]. …”

Section: Methodsmentioning

confidence: 99%

“…MTT assay, annexin V staining and cell cycle analyses were performed as previously described [14,18–20]. For caspase cleavage assays, total protein lysates were prepared from cells at different time points after treatment with bortezomib, and cleavage of caspases 3, 8, and 9 was subsequently examined by immunoblot analysis.…”

Section: Methodsmentioning

confidence: 99%

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Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells

et al. 2016

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Bortezomib, a clinical drug for multiple myeloma (MM) and mantle cell lymphoma, exhibits complex mechanisms of action, which vary depending on the cancer type and the critical genetic alterations of each cancer. Here we investigated the signaling mechanisms of bortezomib in mouse B lymphoma and human MM cells deficient in a new tumor suppressor gene, TRAF3. We found that bortezomib consistently induced up-regulation of the cell cycle inhibitor p21(WAF1) and the pro-apoptotic protein Noxa as well as cleavage of the anti-apoptotic protein Mcl-1. Interestingly, bortezomib induced the activation of NF-κB1 and the accumulation of the oncoprotein c-Myc, but inhibited the activation of NF-κB2. Furthermore, we demonstrated that oridonin (an inhibitor of NF-κB1 and NF-κB2) or AD 198 (a drug targeting c-Myc) drastically potentiated the anti-cancer effects of bortezomib in TRAF3-deficient malignant B cells. Taken together, our findings increase the understanding of the mechanisms of action of bortezomib, which would aid the design of novel bortezomib-based combination therapies. Our results also provide a rationale for clinical evaluation of the combinations of bortezomib and oridonin (or other inhibitors of NF-κB1/2) or AD 198 (or other drugs targeting c-Myc) in the treatment of lymphoma and MM, especially in patients containing TRAF3 deletions or relevant mutations.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Rabbit polyclonal antibody against Noxa was purchased from AXXORA (Farmingdale, NY). Other antibodies and reagents used in this study were described previously [14,18–20]. …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells

et al. 2016

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“…Lentiviruses of MCC expression vectors were packaged and titered as previously described [67,80,87]. Human MM cells were transduced with the packaged lentiviruses at a MOI of 1:5 (cell:virus) in the presence of 8 μg/ml polybrene [13,87,89].…”

Section: Methodsmentioning

confidence: 99%

Mutated in colorectal cancer (MCC) is a novel oncogene in B lymphocytes

Edwards¹,

Baron²,

Moore³

et al. 2014

J Hematol Oncol

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BackgroundIdentification of novel genetic risk factors is imperative for a better understanding of B lymphomagenesis and for the development of novel therapeutic strategies. TRAF3, a critical regulator of B cell survival, was recently recognized as a tumor suppressor gene in B lymphocytes. The present study aimed to identify novel oncogenes involved in malignant transformation of TRAF3-deficient B cells.MethodsWe used microarray analysis to identify genes differentially expressed in TRAF3−/− mouse splenic B lymphomas. We employed lentiviral vector-mediated knockdown or overexpression to manipulate gene expression in human multiple myeloma (MM) cell lines. We analyzed cell apoptosis and proliferation using flow cytometry, and performed biochemical studies to investigate signaling mechanisms. To delineate protein-protein interactions, we applied affinity purification followed by mass spectrometry-based sequencing.ResultsWe identified mutated in colorectal cancer (MCC) as a gene strikingly up-regulated in TRAF3-deficient mouse B lymphomas and human MM cell lines. Aberrant up-regulation of MCC also occurs in a variety of primary human B cell malignancies, including non-Hodgkin lymphoma (NHL) and MM. In contrast, MCC expression was not detected in normal or premalignant TRAF3−/− B cells even after treatment with B cell stimuli, suggesting that aberrant up-regulation of MCC is specifically associated with malignant transformation of B cells. In elucidating the functional roles of MCC in malignant B cells, we found that lentiviral shRNA vector-mediated knockdown of MCC induced apoptosis and inhibited proliferation in human MM cells. Experiments of knockdown and overexpression of MCC allowed us to identify several downstream targets of MCC in human MM cells, including phospho-ERK, c-Myc, p27, cyclin B1, Mcl-1, caspases 8 and 3. Furthermore, we identified 365 proteins (including 326 novel MCC-interactors) in the MCC interactome, among which PARP1 and PHB2 were two hubs of MCC signaling pathways in human MM cells.ConclusionsOur results indicate that in sharp contrast to its tumor suppressive role in colorectal cancer, MCC functions as an oncogene in B cells. Our findings suggest that MCC may serve as a diagnostic marker and therapeutic target in B cell malignancies, including NHL and MM.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0056-6) contains supplementary material, which is available to authorized users.

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Antitumour Anthracyclines: Progress and Perspectives

2020

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Anthracyclines are ranked among the most effective chemotherapeutics against cancer. They are glycoside drugs comprising the amino sugar daunosamine linked to a hydroxy anthraquinone aglycone, and act by DNA intercalation, oxidative stress generation and topoisomerase II poisoning. Regardless of their therapeutic value, multidrug resistance and severe cardiotoxicity are important limitations of anthracycline treatment that have prompted the discovery of novel analogues. This review covers the most clinically relevant anthracyclines and their development over decades, since the first discovered natural prototypes to recent semisynthetic and synthetic derivatives. These include registered drugs, drug candidates undergoing clinical trials, and compounds under pre‐clinical investigation. The impact of the structural modifications on antitumour activity, toxicity and resistance profile is addressed.

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N-benzyladriamycin-14-valerate (AD 198) exhibits potent anti-tumor activity on TRAF3-deficient mouse B lymphoma and human multiple myeloma

Cited by 22 publications

References 54 publications

Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells

Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells

Mutated in colorectal cancer (MCC) is a novel oncogene in B lymphocytes

Antitumour Anthracyclines: Progress and Perspectives

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