Mechanisms underlying synergism between circularized tumor necrosis factor‐related apoptosis inducing ligand and bortezomib in bortezomib‐sensitive or ‐resistant myeloma cells

Leng, Yun; Hu, Xiaoyan; Li, Lin; Nkwocha, Jewel; Satta, Toshihisa; Sharma, Kanika; Kmeiciak, Maciej; Zhou, Huixing; Zhang, Zhiyao; Zhou, Liang; Chen, Wenming; Grant, Steven

doi:10.1002/hon.3045

Cited by 4 publications

(1 citation statement)

References 62 publications

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“…Multiple myeloma (MM) is a clonal disorder of plasma cells accounting for 13% of hematologic malignancies; ~35,000 patients per annum are diagnosed in the USA, with the disease more common in males [1][2][3]. Despite advances in the treatment of MM over the past 10-15 years with the introduction of proteasome inhibitors, e.g., bortezomib (Velcade, BTZ) and subsequently carfilzomib (Kyprolis) and ixazomib (Ninlaro), and more recently with immunomodulatory approaches and antibodies, the median life expectancy of MM patients remains sub-optimal at ~7-8 years [4][5][6]. However, not all myeloma patients respond to proteasome inhibitors and myeloma cells can evolve under this selective proteasome inhibitor pressure to become drug-resistant.…”

Section: Introductionmentioning

confidence: 99%

GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells

Booth,

Roberts,

West

et al. 2024

Oncotarget

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GZ17-6.02, a synthetically manufactured compound containing isovanillin, harmine and curcumin, has undergone phase I evaluation in patients with solid tumors (NCT03775525) with a recommended phase 2 dose (RP2D) of 375 mg PO BID. GZ17-6.02 was more efficacious as a single agent at killing multiple myeloma cells than had previously been observed in solid tumor cell types. GZ17-6.02 interacted with proteasome inhibitors in a greater than additive fashion to kill myeloma cells and alone it killed inhibitor-resistant cells to a similar extent. The drug combination of GZ17-6.02 and bortezomib activated ATM, the AMPK and PERK and inactivated ULK1, mTORC1, eIF2α, NFκB and the Hippo pathway. The combination increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM, and reduced the levels of BCL-XL and MCL1. GZ17-6.02 interacted with bortezomib to enhance autophagosome formation and autophagic flux, and knock down of ATM, AMPKα, ULK1, Beclin1 or ATG5 significantly reduced both autophagy and tumor cell killing. Knock down of BAK and BIM significantly reduced tumor cell killing. The expression of HDACs1/2/3 was significantly reduced beyond that previously observed in solid tumor cells and required autophagy. This was associated with increased acetylation and methylation of histone H3. Combined knock down of HDACs1/2/3 caused activation of ATM and the AMPK and caused inactivation of ULK1, mTORC1, NFκB and the Hippo pathway. HDAC knock down also enhanced ATG13 phosphorylation, increased BAK levels and reduced those of BCL-XL. Collectively, our present studies support performing additional in vivo studies with multiple myeloma cells.

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Section: Introductionmentioning

confidence: 99%

GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells

Booth,

Roberts,

West

et al. 2024

Oncotarget

View full text Add to dashboard Cite

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Mechanisms underlying synergism between circularized tumor necrosis factor‐related apoptosis inducing ligand and bortezomib in bortezomib‐sensitive or ‐resistant myeloma cells

Leng

et al. 2022

Hematological Oncology

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Mechanisms underlying interactions between a novel, clinically relevant circularized tumor necrosis factor-related apoptosis inducing ligand (TRAIL) agonist, circularly permuted TRAIL (CPT) have been examined in multiple myeloma (MM) cells sensitive or resistant to bortezomib (BTZ). Various MM cell lines for example, U266, including those resistant to bortezomib-resistant U266 cells were exposed to low nanomolar concentrations of bortezomib � CPT and apoptosis monitored. Circularly permuted TRAIL and bortezomib synergistically induced apoptosis in both BTZ-naïve and -resistant cells. The regimen up-regulated DR4 receptor internalization in MM cells, known to modulate both NF-κB and extrinsic apoptotic pathways. CPT/BTZ disrupted the non-canonical NF-κB pathway, reflected by tumor necrosis factor (TNF) receptor associated factors 3 (TRAF3) up-regulation, NF-κB inducing kinase down-regulation, diminished p52 and p50 processing, and B-cell lymphoma-extra large (BCL-XL) down-regulation, but failed to inactivate the canonical NF-κB pathway, reflected by unchanged or increased expression of phospho-p65. The regimen also sharply increased extrinsic apoptotic pathway activation. Cells exhibiting TRAF3 knock-down, dominant-negative Fas-associated protein with death domain, knock-down of caspase-8, BCL-2/BCL-XL, or exposure to a caspase-9 inhibitor displayed markedly reduced CPT/BTZ sensitivity. Concordant results were observed in bortezomib-resistant cells. The regimen was also active in the presence of stromal cells and was relatively sparing toward normal CD34 + hematopoietic cells. Finally, ex vivo results revealed synergism in primary MM primary cells, including those BTZ, and the CPT/BTZ regimen significantly

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Non-canonical role for the ataxia-telangiectasia-Rad3 pathway in STAT3 activation in human multiple myeloma cells

Nkwocha

et al. 2023

Cell Oncol.

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Purpose The goal of this study was to characterize the relationship between ATR and STAT3 interactions in human multiple myeloma (MM) cells. Methods Various MM cell lines, including IL-6-dependent cells were exposed to ATR inhibitors and effects on STAT3 Tyr705 and Ser727 were monitored by WB analysis and ImageStream analysis. Parallel studies examined induction of cell death, STAT3 DNA binding activity, and expression of STAT3 downstream targets (BCL-XL, MCL-1, c-MYC). Validation was obtained in ATR shRNA knock-down cells, and in cells ectopically expressing BCL-XL, MCL-1, or c-MYC. Analogous studies were performed in primary MM cells and in a MM xenograft model. Results Multiple pharmacologic ATR inhibitors inhibited STAT3 Tyr705 (but not Ser727) phosphorylation at low uM concentrations and down-regulated BCL-XL, MCL-1, c-MYC in association with cell death induction. Compatible results were observed in ATR shRNA knock-down cells. Cell death induced by ATR inhibitors was significantly attenuated in cells ectopically expressing constitutively active STAT3, BCL-XL, MCL-1, or c-MYC. Concordant results were observed in primary human MM cells and in an in vivo MM xenograft model. Conclusions Collectively, these findings argue for a non-canonical role for the ATR kinase in STAT3 activation in MM cells, and suggest that STAT3 inactivation contributes to the lethal actions of ATR inhibitors in MM.

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Mechanisms underlying synergism between circularized tumor necrosis factor‐related apoptosis inducing ligand and bortezomib in bortezomib‐sensitive or ‐resistant myeloma cells

Cited by 4 publications

References 62 publications

GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells

GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells

Mechanisms underlying synergism between circularized tumor necrosis factor‐related apoptosis inducing ligand and bortezomib in bortezomib‐sensitive or ‐resistant myeloma cells

Non-canonical role for the ataxia-telangiectasia-Rad3 pathway in STAT3 activation in human multiple myeloma cells

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