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Synergistic cytotoxicity of busulfan, melphalan, gemcitabine, panobinostat, and bortezomib in lymphoma cells.

ABSTRACT: DNA alkylators busulfan (B) and melphalan (M) act synergistically with gemcitabine (G) against lymphoma cells. To further improve the cytotoxicity, we combined them with the histone deacetylase inhibitor panobinostat (P) and proteasome inhibitor bortezomib (V). Lymphoma cell lines U937 and J45.01, and patient-derived cell samples were exposed to these drugs and the effects on cell proliferation and apoptosis were quantified. The combination BMGPV was found to exert strong synergistic cytotoxicity. Drug exposure to these cells activated the ATM pathway and modified histones at the epigenetic level. Cell death was triggered by the production of reactive oxygen species (ROS), permeabilization of the mitochondrial membrane, upregulation of proapoptotic factors, and activation of caspases. Downregulation of anti-apoptotic proteins c-MYC, MCL-1, and BCL-2 and inhibition of the prosurvival PI3K-AKT-mTOR pathway, culminated in apoptosis. The results of this study support a clinical trial using BMGPV as a possible pre-transplant conditioning regimen for relapsed/refractory lymphoma patients.

SUBMITTER: Teo EC

PROVIDER: S-EPMC8489015 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Synergistic cytotoxicity of gemcitabine, clofarabine and edelfosine in lymphoma cell lines.

Project description:Treatments for lymphomas include gemcitabine (Gem) and clofarabine (Clo) which inhibit DNA synthesis. To improve their cytotoxicity, we studied their synergism with the alkyl phospholipid edelfosine (Ed). Exposure of the J45.01 and SUP-T1 (T-cell) and the OCI-LY10 (B-cell) lymphoma cell lines to IC10-IC20 levels of the drugs resulted in strong synergistic cytotoxicity for the 3-drug combination based on various assays of cell proliferation and apoptosis. Cell death correlated with increased phosphorylation of histone 2AX and KAP1, decreased mitochondrial transmembrane potential, increased production of reactive oxygen species and release of pro-apoptotic factors. Caspase 8-negative I9.2 cells were considerably more resistant to [Gem+Clo+Ed] than caspase 8-positive cells. In all three cell lines [Gem+Clo+Ed] decreased the level of phosphorylation of the pro-survival protein AKT and activated the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) stress signaling pathway, which in J45.01 cells resulted in the phosphorylation and heterodimerization of the transcription factors ATF2 and c-Jun. The observed rational mechanism-based efficacy of [Gem+Clo+Ed] based on the synergistic convergence of several pro-death and anti-apoptotic signaling pathways in three very different cell backgrounds provides a powerful foundation for undertaking clinical trials of this drug combination for the treatment of lymphomas.

| S-EPMC3913938 | biostudies-other

Bortezomib and gemcitabine in relapsed or refractory Hodgkin's lymphoma.

Project description:BACKGROUND:Given the significant activity and tolerability of gemcitabine in patients with relapsed Hodgkin's lymphoma (HL), the critical role that nuclear factor kappa B (NF-kappaB) appears to play in the pathogenesis of this tumor, the ability of bortezomib to inhibit NF-kappaB activity, and laboratory studies suggesting synergistic antitumor effects of gemcitabine and bortezomib, we hypothesized that this combination would be efficacious in patients with relapsed or refractory HL. PATIENTS AND METHODS:A total of 18 patients participated. Patients received 3-week cycles of bortezomib 1 mg/m(2) on days 1, 4, 8, and 11 plus gemcitabine 800 mg/m(2) on days 1 and 8. RESULTS:The overall response rate for all patients was 22% (95% confidence interval 3% to 42%). Three patients developed grade III transaminase elevation: one was removed from the study and two had doses of gemcitabine held. Almost all patients exhibited inhibition of proteasome activity with treatment. CONCLUSIONS:The combination of gemcitabine and bortezomib is a less active and more toxic regimen in relapsed HL than other currently available treatments. It poses a risk of severe liver toxicity and should be pursued with caution in other types of cancer.

| S-EPMC2735068 | biostudies-literature

High-dose gemcitabine, busulfan, and melphalan for autologous stem-cell transplant in patients with relapsed or refractory myeloma: a phase 2 trial and matched-pair comparison with melphalan.

Project description: Not available

| S-EPMC5844223 | biostudies-literature

Busulfan, melphalan, and bortezomib compared to melphalan as a high dose regimen for autologous hematopoietic stem cell transplantation in multiple myeloma: long term follow up of a novel high dose regimen.

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| S-EPMC7786301 | biostudies-literature

Synergistic anticancer effects of arsenic trioxide with bortezomib in mantle cell lymphoma.

Project description:Mantle cell lymphoma (MCL) is a subtype of B-cell Non-Hodgkin's Lymphoma (NHL) and accounts for ~6% of all lymphomas. MCL is highly refractory to most chemotherapy including newer antibody-based therapeutic approaches, and high-grade MCL has one of the worst survival rates among NHLs. Therefore, the development of new therapeutic strategies to overcome drug resistance of MCL is important. In this article, we tested the effects of arsenic trioxide (As(2) O(3) , ATO) in bortezomib-resistant MCL. ATO is reported to induce complete remission in the patients with relapsed or refractory acute promyelocytic leukemia. Their effects in MCL, however, have not been explored. In this report, we show that ATO effectively inhibited the growth of MCL cells in vitro. ATO treatment also reduced cyclin D1 expression which is a genetic hallmark of MCL and NF-kB expression which was reported to have a prosurvival role in some MCL cells. The induction of apoptosis in MCL was partially due to reduced levels of cyclin D1 and increased levels of apoptosis-related molecules. The antiproliferative effects of bortezomib on MCL greatly increased when the cells were also treated with ATO, indicating ATO can sensitize MCL to bortezomib. Similar results were noted in bortezomib-resistant cell lines. In conclusion, ATO may be an alternative drug for use in combined adjuvant therapies for MCL, and further clinical testing should be performed.

| S-EPMC3894928 | biostudies-literature

In vitro synergistic cytotoxicity of gemcitabine and pemetrexed and pharmacogenetic evaluation of response to gemcitabine in bladder cancer patients.

Project description:The present study was performed to investigate the capability of gemcitabine and pemetrexed to synergistically interact with respect to cytotoxicity and apoptosis in T24 and J82 bladder cancer cells, and to establish a correlation between drug activity and gene expression of selected genes in tumour samples. The interaction between gemcitabine and pemetrexed was synergistic; indeed, pemetrexed favoured gemcitabine cytotoxicity by increasing cellular population in S-phase, reducing Akt phosphorylation as well as by inducing the expression of a major gemcitabine uptake system, the human equilibrative nucleoside transporter-1 (hENT1), and the key activating enzyme deoxycytidine kinase (dCK) in both cell lines. Bladder tumour specimens showed an heterogeneous gene expression pattern and patients with higher levels of dCK and hENT1 had better response. Moreover, human nucleoside concentrative transporter-1 was detectable only in 3/12 patients, two of whom presented a complete response to gemcitabine. These data provide evidence that the chemotherapeutic activity of the combination of gemcitabine and pemetrexed is synergistic against bladder cancer cells in vitro and that the assessment of the expression of genes involved in gemcitabine uptake and activation might be a possible determinant of bladder cancer response and may represent a new tool for treatment optimization.

| S-EPMC2360654 | biostudies-literature

Role of CAAT/enhancer binding protein homologous protein in panobinostat-mediated potentiation of bortezomib-induced lethal endoplasmic reticulum stress in mantle cell lymphoma cells.

Project description:PURPOSE:Bortezomib induces unfolded protein response (UPR) and endoplasmic reticulum stress, as well as exhibits clinical activity in patients with relapsed and refractory mantle cell lymphoma (MCL). Here, we determined the molecular basis of the improved in vitro and in vivo activity of the combination of the pan-histone deacetylase inhibitor panobinostat and bortezomib against human, cultured, and primary MCL cells. EXPERIMENTAL DESIGN:Immunoblot analyses, reverse transcription-PCR, and immunofluorescent and electron microscopy were used to determine the effects of panobinostat on bortezomib-induced aggresome formation and endoplasmic reticulum stress in MCL cells. RESULTS:Treatment with panobinostat induced heat shock protein 90 acetylation; depleted the levels of heat shock protein 90 client proteins, cyclin-dependent kinase 4, c-RAF, and AKT; and abrogated bortezomib-induced aggresome formation in MCL cells. Panobinostat also induced lethal UPR, associated with induction of CAAT/enhancer binding protein homologous protein (CHOP). Conversely, knockdown of CHOP attenuated panobinostat-induced cell death of MCL cells. Compared with each agent alone, cotreatment with panobinostat increased bortezomib-induced expression of CHOP and NOXA, as well as increased bortezomib-induced UPR and apoptosis of cultured and primary MCL cells. Cotreatment with panobinostat also increased bortezomib-mediated in vivo tumor growth inhibition and improved survival of mice bearing human Z138C MCL cell xenograft. CONCLUSION:These findings suggest that increased UPR and induction of CHOP are involved in enhanced anti-MCL activity of the combination of panobinostat and bortezomib.

| S-EPMC2948590 | biostudies-literature

Busulfan and melphalan conditioning is superior to melphalan alone in autologous stem cell transplantation for high-risk MM.

Project description: Not available

| S-EPMC7556152 | biostudies-literature

Intracellular glutathione determines bortezomib cytotoxicity in multiple myeloma cells.

Project description:Multiple myeloma (myeloma in short) is an incurable cancer of antibody-producing plasma cells that comprise 13% of all hematological malignancies. The proteasome inhibitor bortezomib has improved treatment significantly, but inherent and acquired resistance to the drug remains a problem. We here show that bortezomib-induced cytotoxicity was completely dampened when cells were supplemented with cysteine or its derivative, glutathione (GSH) in ANBL-6 and INA-6 myeloma cell lines. GSH is a major component of the antioxidative defense in eukaryotic cells. Increasing intracellular GSH levels fully abolished bortezomib-induced cytotoxicity and transcriptional changes. Elevated intracellular GSH levels blocked bortezomib-induced nuclear factor erythroid 2-related factor 2 (NFE2L2, NRF2)-associated stress responses, including upregulation of the xCT subunit of the Xc- cystine-glutamate antiporter. INA-6 cells conditioned to increasing bortezomib doses displayed reduced bortezomib sensitivity and elevated xCT levels. Inhibiting Xc- activity potentiated bortezomib-induced cytotoxicity in myeloma cell lines and primary cells, and re-established sensitivity to bortezomib in bortezomib-conditioned cells. We propose that intracellular GSH level is the main determinant of bortezomib-induced cytotoxicity in a subset of myeloma cells, and that combined targeting of the proteasome and the Xc- cystine-glutamate antiporter can circumvent bortezomib resistance.

| S-EPMC5141348 | biostudies-literature

Epigenetic modification enhances the cytotoxicity of busulfan and4-hydroperoxycyclophosphamide in AML cells.

Project description:The combination of the DNA-alkylating agents busulfan (Bu) and cyclophosphamide is the most commonly used myeloablative pretransplantation conditioning therapy for myeloid leukemias. However, it is associated with significant nonrelapse mortality, which prohibits dose escalation to control relapse. We hypothesized that combining these two drugs with an epigenetic modifier would increase antileukemic efficacy without jeopardizing patient safety. A preclinical study was performed to determine the synergistic cytotoxicity of Bu, 4-hydroperoxycyclophosphamide (4HC), and the hypomethylating agent decitabine (DAC) in human acute myeloid leukemia (AML) cell lines. Exposure of KBM3/Bu2506 (P53-null) and OCI-AML3 (P53-wild-type) cells to Bu+4HC inhibited cell proliferation by ∼35-39%; addition of DAC increased the inhibition to ∼60-62%. The observed synergistic interactions correlated with DNA damage response activation, increased the production of reactive oxygen species, and decreased mitochondrial membrane potential, release of mitochondrial proapoptotic proteins into the cytoplasm, and induction of caspase-dependent programmed cell death. The Bu+4HC+DAC combination further caused chromatin trapping of DNMT1 with a concomitant increase in DNA damage. In contrast, FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD)-positive AML cell lines were not sensitized to Bu+4HC by inclusion of DAC; addition of the FLT3 kinase inhibitor sorafenib sensitized the FLT3-ITD-positive MV4-11 and MOLM13 cell lines to the triple drug combination by inhibiting the FLT3 signal transduction pathway. Our results therefore provide a rationale for the development of personalized conditioning therapy for patients with P53-mutated and FLT3-ITD-positive AML.

| S-EPMC6262883 | biostudies-literature

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