Crucial role of HO-1/IRF4-dependent apoptosis induced by panobinostat and lenalidomide in multiple myeloma

Tang, Sishi; Ma, Dan; Cheng, Bingqing; Fang, Qing; Kuang, Xingyi; Yu, Kunling; Wang, Weili; Hu, Bo; Wang, Jishi

doi:10.1016/j.yexcr.2018.01.005

Cited by 21 publications

(18 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The optimal dose and schedule of pano-Vd was confirmed in the randomized phase 3 PANORAMA 3 trial as 20 mg thrice weekly; DOR with this regimen was 22.6 months and tolerability was improved with subcutaneous administration of bortezomib with only 11.5% of patients in the 20 mg TIW dosing group reporting grade 3/4 diarrhea compared with intravenous delivery of bortezomib, as was standard practice at the time of previous clinical trials. 16 Broad-spectrum HDACis also enhance the anti-MM activity of IMiDs, such as lenalidomide, by suppressing diverse oncogenic transcriptional programs 10 , including the interferon regulatory factor-4/MYC axis 17 . In a phase 2 study of patients with RRMM, panobinostat plus lenalidomide and dexamethasone (pano-Rd) demonstrated an encouraging ORR (41%) and median PFS (7.1 months) in patients with high-risk, lenalidomide-refractory (81%), and/or bortezomib-refractory (52%) MM, suggesting that panobinostat is also able to overcome resistance to IMiDs.…”

Section: Introductionmentioning

confidence: 99%

Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma

et al. 2021

View full text Add to dashboard Cite

Additional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50–77]) and a median of four prior regimens (range: 2–14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1–74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.

show abstract

Section: Introductionmentioning

confidence: 99%

Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma

et al. 2021

View full text Add to dashboard Cite

show abstract

“…These findings are consistent with those previous studies that demonstrated the collaborative anti-myeloma effect of HDAC inhibitor combined with lenalidomide. [34][35][36] Lenalidomide acts primarily through the inhibition of peroxidase-mediated decomposition of intracellular H 2 O 2 (an important form of ROS 6 ) in MM cells. 11 H 2 O 2 -mediated oxidative stress causes CRBN-dependent degradation of IKZF1 and IKZF3, which is the main mechanism associated with lenalidomide-mediated cytotoxicity in MM.…”

Section: Discussionmentioning

confidence: 99%

Chidamide-Induced Accumulation of Reactive Oxygen Species Increases Lenalidomide Sensitivity Against Multiple Myeloma Cells

Jiang¹,

Zhang²,

Zhu³

et al. 2021

OTT

View full text Add to dashboard Cite

Background: Lenalidomide, an immunomodulatory drug (IMiD), is an effective therapy for the treatment of multiple myeloma (MM). However, prolonged treatment may be accompanied by toxicity, second primary malignancies, and drug resistance. There is an inherent vulnerability in MM cells that high rates of immunoglobulin synthesis resulting in the high level of reactive oxygen species (ROS). This provides a therapeutic potential for MM. Materials and Methods: The intracellular ROS levels, H 2 O 2 production and glutathione (GSH) levels were measured using detection kit. Cell viability was evaluated using cell-counting kit-8 (CCK-8) and soft agar colony formation assay. Apoptosis was determined in whole living cells using flow cytometry. Chidamide and its anti-myeloma efficacy in combination with lenalidomide were characterized in MM cell lines in vitro and in a mouse xenograft model. Moreover, Western blotting, immunofluorescence and immunohistochemical studies were performed. Results: ROS levels increased in a time-and dose-dependent manner with chidamide treatment. Moreover, the GSH levels were decreased and the mRNA level of SLC7A11 downregulated after chidamide treatment. The co-treatment with chidamide and lenalidomide increased apoptosis and proliferation inhibition, with combination index (CI) in the synergistic range (0.2-0.5) using the Chou-Talalay method. The cooperative anti-myeloma efficacy was confirmed in the murine model, and immunohistochemical studies also supported this potentiation. Chidamide enhanced the effect of lenalidomide-induced degradation of IKZF1 and IKZF3 by elevating H 2 O 2 . In addition, co-treatment with chidamide and lenalidomide increased biomarkers of caspase and DNA damage. Conclusion: Elevated ROS production may constitute a potential biochemical basis for antimyeloma effects of chidamide plus lenalidomide. The results of this study confirm the synergistic effect of chidamide and lenalidomide against MM and provide a promising therapeutic strategy for MM.

show abstract

“…A combination of panobinostat and bortezomib exerts a complementary inhibitory effect on protein degradation systems, including proteasome and aggresome; the latter is inhibited through HDAC6, a master regulator of the cell response to cytotoxic misfolded proteins [ 256 , 262 ]. Panobinostat induces acetylation of histones H3 and H4, activation of caspases 3 and 8, and reduces the levels of the transcription factors IRF4 and MYC [ 263 , 264 ]. MYC is a well-known oncogene that is deregulated in many cancers, including MM.…”

Section: Clinical Manifestation Of Multiple Myeloma and Recent Research Approachesmentioning

confidence: 99%

Genome Instability in Multiple Myeloma: Facts and Factors

Aksenova

Zhuk

Lada

et al. 2021

Cancers

View full text Add to dashboard Cite

Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete understanding. Genetically, MM is a complex disease that demonstrates a high level of heterogeneity. Myeloma genomes carry numerous genetic changes, including structural genome variations and chromosomal gains and losses, and these changes occur in combinations with point mutations affecting various cellular pathways, including genome maintenance. MM genome instability in its extreme is manifested in mutation kataegis and complex genomic rearrangements: chromothripsis, templated insertions, and chromoplexy. Chemotherapeutic agents used to treat MM add another level of complexity because many of them exacerbate genome instability. Genome abnormalities are driver events and deciphering their mechanisms will help understand the causes of MM and play a pivotal role in developing new therapies.

show abstract

Crucial role of HO-1/IRF4-dependent apoptosis induced by panobinostat and lenalidomide in multiple myeloma

Cited by 21 publications

References 32 publications

Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma

Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma

Chidamide-Induced Accumulation of Reactive Oxygen Species Increases Lenalidomide Sensitivity Against Multiple Myeloma Cells

Genome Instability in Multiple Myeloma: Facts and Factors

Contact Info

Product

Resources

About