scholarly journals Promising Anti-Mitochondrial Agents for Overcoming Acquired Drug Resistance in Multiple Myeloma

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 439
Author(s):  
Vanessa Innao ◽  
Vincenzo Rizzo ◽  
Andrea Gaetano Allegra ◽  
Caterina Musolino ◽  
Alessandro Allegra
Keyword(s):  
Oxidative Stress ◽  
Multiple Myeloma ◽  
Drug Resistance ◽  
Proteasome Inhibitors ◽  
High Rate ◽  
Acquired Drug Resistance ◽  
Smac Mimetics ◽  
Stress Result ◽  
New Compounds ◽  
Glutaminase 1

Multiple myeloma (MM) remains an incurable tumor due to the high rate of relapse that still occurs. Acquired drug resistance represents the most challenging obstacle to the extension of survival and several studies have been conducted to understand the mechanisms of this phenomenon. Mitochondrial pathways have been extensively investigated, demonstrating that cancer cells become resistant to drugs by reprogramming their metabolic assessment. MM cells acquire resistance to proteasome inhibitors (PIs), activating protection programs, such as a reduction in oxidative stress, down-regulating pro-apoptotic, and up-regulating anti-apoptotic signals. Knowledge of the mechanisms through which tumor cells escape control of the immune system and acquire resistance to drugs has led to the creation of new compounds that can restore the response by leading to cell death. In this scenario, based on all literature data available, our review represents the first collection of anti-mitochondrial compounds able to overcome drug resistance in MM. Caspase-independent mechanisms, mainly based on increased oxidative stress, result from 2-methoxyestradiol, Artesunate, ascorbic acid, Dihydroartemisinin, Evodiamine, b-AP15, VLX1570, Erw-ASNase, and TAK-242. Other agents restore PIs’ efficacy through caspase-dependent tools, such as CDDO-Im, NOXA-inhibitors, FTY720, GCS-100, LBH589, a derivative of ellipticine, AT-101, KD5170, SMAC-mimetics, glutaminase-1 (GLS1)-inhibitors, and thenoyltrifluoroacetone. Each of these substances improved the efficacy rates when employed in combination with the most frequently used antimyeloma drugs.

scholarly journals Treatment Strategies Considering Micro-Environment and Clonal Evolution in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 215
Author(s):  
Kazuhito Suzuki ◽  
Kaichi Nishiwaki ◽  
Shingo Yano
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
De Novo ◽  
Clonal Evolution ◽  
Proteasome Inhibitors ◽  
Treatment Strategies ◽  
Neutral Evolution ◽  
Acquired Drug Resistance ◽  
Immunological Surveillance

Multiple myeloma is an uncurable hematological malignancy because of obtained drug resistance. Microenvironment and clonal evolution induce myeloma cells to develop de novo and acquired drug resistance, respectively. Cell adhesion-mediated drug resistance, which is induced by the interaction between myeloma and bone marrow stromal cells, and soluble factor-mediated drug resistance, which is induced by cytokines and growth factors, are two types of de novo drug resistance. The microenvironment, including conditions such as hypoxia, vascular and endosteal niches, contributes toward de novo drug resistance. Clonal evolution was associated with acquired drug resistance and classified as branching, linear, and neutral evolutions. The branching evolution is dependent on the microenvironment and escape of immunological surveillance while the linear and neutral evolution is independent of the microenvironment and associated with aggressive recurrence and poor prognosis. Proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibody agents (MoAbs), and autologous stem cell transplantation (ASCT) have improved prognosis of myeloma via improvement of the microenvironment. The initial treatment plays the most important role considering de novo and acquired drug resistance and should contain PIs, IMIDs, MoAb and ASCT. This review summarizes the role of anti-myeloma agents for microenvironment and clonal evolution and treatment strategies to overcome drug resistance.

scholarly journals Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Liu ◽  
Ying Xie ◽  
Jing Guo ◽  
Xin Li ◽  
Jingjing Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Acquired Drug Resistance ◽  
Bortezomib Treatment ◽  
Liquid Liquid Phase Separation

AbstractDevelopment of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid–liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.

Deacetylation Induced Nuclear Condensation of HP1γ Promotes Multiple Myeloma Drug Resistance

2021 ◽  
Author(s):  
Zhiqiang Liu ◽  
Xin Li ◽  
Sheng Wang ◽  
Ying Xie ◽  
Hongmei Jiang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Drug Resistance ◽  
Heterochromatin Protein 1 ◽  
Nuclear Condensation ◽  
Repair Capacity ◽  
Acquired Drug Resistance ◽  
Histone Deacetylase 1

Abstract Acquired chemoresistance to proteasome inhibitors (PIs) is a major obstacle that results in failure to manage patients with multiple myeloma (MM) in the clinic; however, the key regulators and underlying mechanisms are still unclear. In this study, we found that high levels of a chromosomal modifier, heterochromatin protein 1 gamma (HP1γ), are accompanied by a low acetylation level in bortezomib-resistant (BR) MM cells, and aberrant DNA repair capacity is correlated with HP1γ overexpression. Mechanistically, the deacetylation of HP1γ at lysine 5 by histone deacetylase 1 (HDAC1) alleviates HP1γ ubiquitination, and the stabilized HP1γ recruits the mediator of DNA damage checkpoint 1 (MDC1) to induce DNA damage repair. Simultaneously, deacetylation modification and MDC1 recruitment enhance the nuclear condensate of HP1γ, which facilitates the chromatin accessibility of genes governing sensitivity to PIs, such as FOS, JUN and CD40. Thus, targeting HP1γ stability using the HDAC1/2 inhibitor, romidepsin, sensitizes PIs treatment and overcomes drug resistance both in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in the acquired drug resistance of MM and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in MM patients.

scholarly journals Measurement of ex vivo resistance to proteasome inhibitors, IMiDs, and daratumumab during multiple myeloma progression

2020 ◽  
Vol 4 (8) ◽  
pp. 1628-1639
Author(s):  
Zachary J. Walker ◽  
Michael J. VanWyngarden ◽  
Brett M. Stevens ◽  
Diana Abbott ◽  
Andrew Hammes ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clinical Response ◽  
Drug Sensitivity ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Proteasome Inhibitors ◽  
Clinical Test ◽  
Sensitivity Testing ◽  
Acquired Drug Resistance

Abstract The oncogenic drivers and progression factors in multiple myeloma (MM) are heterogeneous and difficult to target therapeutically. Many different MM drugs have emerged, however, that attack various phenotypic aspects of malignant plasma cells. These drugs are administered in numerous, seemingly interchangeable combinations. Although the availability of many treatment options is useful, no clinical test capable of optimizing and sequencing the treatment regimens for an individual patient is currently available. To overcome this problem, we developed a functional ex vivo approach to measure patients’ inherent and acquired drug resistance. This method, which we termed myeloma drug sensitivity testing (My-DST), uses unselected bone marrow mononuclear cells with a panel of drugs in clinical use, followed by flow cytometry to measure myeloma-specific cytotoxicity. We found that using whole bone marrow cultures helped preserve primary MM cell viability. My-DST was used to profile 55 primary samples at diagnosis or at relapse. Sensitivity or resistance to each drug was determined from the change in MM viability relative to untreated control samples. My-DST identified progressive loss of sensitivity to immunomodulatory drugs, proteasome inhibitors, and daratumumab through the disease course, mirroring the clinical development of resistance. Prospectively, patients’ ex vivo drug sensitivity to the drugs subsequently received was sensitive and specific for clinical response. In addition, treatment with <2 drugs identified as sensitive by My-DST led to inferior depth and duration of clinical response. In summary, ex vivo drug sensitivity is prognostically impactful and, with further validation, may facilitate more personalized and effective therapeutic regimens.

scholarly journals Chromosomal instability and acquired drug resistance in multiple myeloma

Oncotarget ◽  
2017 ◽  
Vol 8 (44) ◽  
pp. 78234-78244 ◽  
Author(s):  
Wang Wang ◽  
Yi Zhang ◽  
Ruini Chen ◽  
Zhidan Tian ◽  
Yongpin Zhai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Chromosomal Instability ◽  
Acquired Drug Resistance

scholarly journals DKK1 activates noncanonical NF-κB signaling via IL-6–induced CKAP4 receptor in multiple myeloma

2021 ◽  
Vol 5 (18) ◽  
pp. 3656-3667
Author(s):  
Xin Li ◽  
Jingjing Wang ◽  
Shuai Zhu ◽  
Jinxin Zheng ◽  
Ying Xie ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Wnt Signaling ◽  
Proteasome Inhibitors ◽  
Bone Destruction ◽  
Bortezomib Treatment ◽  
Canonical Wnt ◽  
Dickkopf 1

Abstract Proteasome inhibitors, such as bortezomib (BTZ), represent the key elements in chemotherapy regimens for multiple myeloma (MM), whereas acquired chemoresistance and ultimately relapse remain a major obstacle. In the current study, we screened differently expressed cytokines in bortezomib-resistant MM cells and found that Dickkopf-1 (DKK1) level was remarkably augmented, whereas CD138 level was significantly suppressed. DKK1 in vitro specifically enhanced the resistance of myeloma cells to bortezomib treatment, and excessive DKK1 drove CD138 downregulation via inhibition of canonical Wnt signaling. Notably, DKK1 mainly induced drug resistance in MM cells via the receptor of CKAP4. Mechanistically, CKAP4 transduced DKK1 signal and evoked NF-κB pathway through recruiting and preventing cullin associated and neddylation dissociated 1 from hampering the assembly of E3 ligase-mediated ubiquitination of IκBα. In addition, we found that interleukin-6 (IL-6) stimulated CKAP4 expression to generate drug resistance, and disturbance of DKK1-CKAP4 axis improved sensitivity to BTZ treatment of MM and attenuated bone destruction in a mouse model. Collectively, our study revealed the previously unidentified role of DKK1 in myeloma drug resistance via Wnt signaling dependent and independent manners, and clarified the importance of antagonism of DKK1-IL-6 loop in bone marrow microenvironment.

The conundrum of dietary antioxidants in cancer chemotherapy

2019 ◽  
Vol 78 (1) ◽  
pp. 65-76 ◽  
Author(s):  
Roghayeh Ilghami ◽  
Abolfazl Barzegari ◽  
Mohammad Reza Mashayekhi ◽  
Didier Letourneur ◽  
Michel Crepin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Drug Resistance ◽  
Side Effects ◽  
Cancer Chemotherapy ◽  
Dietary Antioxidants ◽  
Normal Cells ◽  
Acquired Drug Resistance ◽  
Redox Biology ◽  
Response To Chemotherapy ◽  
Cancer Dormancy

Abstract Although chemotherapy succeeds in reducing tumor burden, the efficacy is limited due to acquired drug resistance and often irreparable side effects. Studies show that antioxidants may influence the response to chemotherapy and its side effects, although their use remains controversial. The evidence shows that some chemo-drugs induce oxidative stress and lead to normal tissue apoptosis and the entry of cancer cells to a dormant G0 state. Through the suppression of oxidative stress, antioxidants could protect normal cells and bring the tumor out of dormancy so as to expose it to chemotherapies. This review is focused on the redox biology of cancer/normal cells and association of reactive oxygen species with drug resistance, cancer dormancy, and side effects. To this end, evidence from cellular, animal, and clinical studies is provided to better understand the conundrum of dietary antioxidants in cancer chemotherapy.

Phosphatidylinositol 3-kinase signaling inhibitors for treatment of multiple myeloma: From small molecules to microRNAs

2021 ◽  
pp. 107815522110353
Author(s):  
Mahshid Mehdizadeh ◽  
Behrouz Farhadihosseinabadi ◽  
Maryam Nikoonezhad ◽  
Ghazaleh Sankanian ◽  
Masoud Soleimani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Small Molecules ◽  
Signaling Pathways ◽  
High Rate ◽  
Kinase Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Signaling Inhibitors ◽  
Effective Drugs ◽  
Phosphatidylinositol 3

Multiple myeloma is one of the most hard-to-treat cancers among blood malignancies due to the high rate of drug resistance and relapse. The researchers are trying to find more effective drugs for treatment of the disease. Hence, the use of drugs targeting signaling pathways has become a powerful weapon. Overactivation of phosphatidylinositol 3-kinase signaling pathways is frequently observed in multiple myeloma cancer cells, which increases survival, proliferation, and even drug resistance in such cells. In recent years, drugs that inhibit the mediators involved in this biological pathway have shown promising results in the treatment of multiple myeloma. In the present study, we aimed to introduce phosphatidylinositol 3-kinase signaling inhibitors which include small molecules, herbal compounds, and microRNAs.

NF-kB as a Regulator of FA/BRCA Gene Expression in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3508-3508
Author(s):  
Vasco A. Oliveira ◽  
Linda Mathews ◽  
Danielle Yarde ◽  
Xingyu Wang ◽  
David Boulware ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Drug Resistance ◽  
Dna Binding ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Binding Activity ◽  
Acquired Drug Resistance ◽  
Brca Gene ◽  
Dna Binding Activity

Abstract Results to date argue compellingly that disruption of FA/BRCA gene expression plays a pivotal role in human somatic carcinogenesis. Melphalan, a DNA cross-linker, is one of the most widely used and effective drugs in the treatment of multiple myeloma (MM). Although most patients respond to standard and high dose melphalan, eventually patients acquire resistance and develop progressive disease. In 1991, our laboratory reported that acquired resistance in a human myeloma cell line was associated with reduced DNA crosslinks, elevated glutathione levels, and increased radiation survival (Cancer Res. 5:993; 1991). Most recently, we reported that the melphalan-resistant myeloma cell lines, 8226/LR5 and U266/LR6, showed a significant increase in several FA/BRCA genes compared to drug-sensitive cells, and that enhanced interstrand crosslink (ICL) repair via this signaling pathway contributes to acquired drug resistance in melphalan resistant cell lines (Blood 10:698; 2005). Here, we report that IKKa is constitutively phosphorylated in unstimulated 8226/LR5 cells, but not in melphalan-sensitive control cells. The specific phosphorylation of IKKa leads to an increase in basal NF-kB DNA binding activity, and 8226/LR5 cells are found to be markedly sensitive to BMS-345541 (a highly selective inhibitor of IkB) relative to control cells. Importantly, a cytotoxic dose of BMS-345541 induces a dramatic decrease in FA/BRCA gene expression, and a concomitant inhibition of NF-kB DNA binding activity in both 8226/S and 8226/LR5 cells. Furthermore, we show that 8226/LR5 cells experience the highest degree of direct binding between FANCD2 promoter and NF-kB/Rel family members, which, in turn, leads to an increase in basal FANCD2-specific NF-kB activity. Small-interfering RNA (siRNA)-mediated depletion of RelB and p50, but not other NF-kB subunits, in 8226 cells results in impaired NF-kB binding activity, and visible decrease in FANCD2 protein expression. Studies designed to dissect the role of NF-kB in acquired melphalan resistance are in progress, and the results will be presented. Our findings suggest that NF-kB functions as a regulator of FA/BRCA expression, and that this pathway represents a new target for preventing acquired drug resistance in myeloma patients.

High rate of virological failure and HIV drug resistance in semi-rural Gabon and implications for dolutegravir-based regimen efficacy

2020 ◽  
Author(s):  
Jéordy D Engone-Ondo ◽  
Augustin Mouinga-Ondémé ◽  
Sonia E Lékana-Douki ◽  
Abdoulaye Diané ◽  
Antony I Mamimandjiami ◽  
...  
Keyword(s):  
Drug Resistance ◽  
High Rate ◽  
Resistance Mutations ◽  
First Line ◽  
Rural Regions ◽  
Hiv Drug Resistance ◽  
Acquired Drug Resistance ◽  
Resource Limited ◽  
Study Population ◽  
Study Participants

Abstract Background The projected UNAIDS goal of ending AIDS by 2030 requires significant global efforts to improve current and future ART strategies. In this study, we assessed viral load (VL) suppression and acquired drug resistance, as well as future efficacy of dolutegravir-based combinations for patients living in semi-rural regions of Gabon. Methods Eligible study participants were adults receiving ART and recruited between 2018 and 2019 in Franceville, Gabon. VL testing was conducted to assess VL suppression and HIV drug resistance (HIVDR) testing was performed to identify resistance mutations and assess their impact on ongoing and future ART regimens. Results We recruited 219 participants overall. The median time on ART was 27 months and 216/219 participants were on first-line ART. VL suppression (VL < 1000 copies/mL) was 57.1% (95% CI 50.5–63.8) overall; 59.4% (51.4–67.5) and 52.2% (40.3–64.2) for women and men, respectively. The overall prevalence of HIVDR was 21.9% among the study population and 67.2% among those who failed ART. Presence of both NRTI and NNRTI mutations was found in 84.6% of sequences with drug resistance mutations, and full activity of a dolutegravir-based first-line regimen including tenofovir disoproxil fumarate/lamivudine/dolutegravir was expected only for 5/39 patients with a resistant virus. Conclusions This study shows a very low rate of VL suppression in a semi-rural context in Africa. Moreover, the high burden of HIVDR has affected both current and newly recommended ART strategies. Better management of ART in resource-limited settings is still a challenging ambition.

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