Cladribine, gemcitabine, busulfan, and SAHA combination as a potential pretransplant conditioning regimen for lymphomas: A preclinical study

Ji, Jie; Valdez, Benigno C.; Li, Yang; Liu, Yan; Teo, Esmeralda C.; Nieto, Yago; Champlin, Richard E.; Andersson, Börje S.

doi:10.1016/j.exphem.2016.03.001

Cited by 7 publications

(8 citation statements)

References 31 publications

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“…The synergistic effect of the chidamide, cladribine, gemcitabine, and busulfan combination was confirmed in previous research ( 9 ), which found that HDACi combined with CGB synergistically inhibited lymphoma cells in a certain order of medication administration. HDACi increased the sensitivity of genomic DNA to busulfan crosslinking via loosening and opening DNA.…”

Section: Discussionsupporting

confidence: 76%

“…In our previous work, we demonstrated that cladribine, gemcitabine, and busulfan (CGB) had a synergistic effect on killing lymphoma cells, and a histone deacetylase inhibitor (HDACi), vorinostat, sensitized the lymphoma cells to the CGB regimen by causing changes in the chromatin structure ( 9 ). Another HDACi, chidamide, inhibits HDAC 1, 2, 3, and 10 and is an oral agent approved by the National Medical Products Administration (NMPA) of China for refractory/relapsed PTCL, also synergized with CGB in killing lymphoma cells.…”

Section: Introductionmentioning

confidence: 99%

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A novel conditioning regimen of chidamide, cladribine, gemcitabine, and busulfan in the autologous stem cell transplantation of aggressive T-cell lymphoma

et al. 2023

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BackgroundThe prognosis of patients with peripheral T-cell (PTCL) or lymphoblastic T-cell lymphoma (T-LBL) remains poor under current conditioning regimens before receiving autologous stem cell transplantation (ASCT).MethodsPatients with PTCL or T-LBL were enrolled to receive ASCT using the conditioning regimen of chidamide, cladribine, gemcitabine, and busulfan (ChiCGB). Positron emission tomography-computed tomography (PET/CT) was used to evaluate the response to ASCT. Overall survival (OS) and progression-free survival (PFS) were employed to assess the patient outcome, and adverse events were used to assess the regimen’s safety. The survival curve was estimated via the Kaplan-Meier method.ResultsTwenty-five PTCL and 11 T-LBL patients were recruited. The median time to neutrophile and platelet engraftments was 10 days (8–13 days) and 13 days (9–31 days), respectively. The 3-year PFS and OS were 81.3 ± 7.2% and 88.5 ± 5.4% for all patients; 92.0 ± 5.4% and 81.2 ± 8.8% for PTCL patients; and both 81.8 ± 11.6% for T-LBL patients, respectively. The 3-year PFS and OS were both 92.9 ± 4.9% for patients with complete response (CR) but 50.0 ± 17.7% and 75.0 ± 15.3% for patients with non-CR, respectively. Infection was the most common non-hematological toxicity, and all toxicities were mild and controllable.ConclusionsChiCGB was a potentially effective and well-tolerated conditioning regimen to improve the prognosis of patients with aggressive T-cell lymphoma. Future randomized controlled trials are needed to assess ChiCGB as a conditioning regimen for ASCT.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

A novel conditioning regimen of chidamide, cladribine, gemcitabine, and busulfan in the autologous stem cell transplantation of aggressive T-cell lymphoma

et al. 2023

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“…SAHA was part of a combination with two antimetabolites, cladribine and Gemcitabine and an alkylating agent, busulfan. This preclinical study in lymphoma cell lines demonstrated that any increase in cytotoxicity could be attributed to stable chromatin relaxation mediated by the antimetabolites and SAHA, thereby increasing the susceptibility of genomic DNA to busulfan alkylation (Ji et al, 2016). SAHA was also used in a multitherapy approach in clinical trials.…”

Section: Hdacis and Multitherapymentioning

confidence: 95%

Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for Clinical Trials

et al. 2020

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Chemotherapy is one of the most established and effective treatments for almost all types of cancer. However, the elevated toxicity due to the non-tumor-associated effects, development of secondary malignancies, infertility, radiation-induced fibrosis and resistance to treatment limit the effectiveness and safety of treatment. In addition, these multiple factors significantly impact quality of life. Over the last decades, our increased understanding of cancer epigenetics has led to new therapeutic approaches and the promise of improved patient outcomes. Epigenetic alterations are commonly found in cancer, especially the increased expression and activity of histone deacetylases (HDACs). Dysregulation of HDACs are critical to the development and progression of the majority of tumors. Hence, HDACs inhibitors (HDACis) were developed and now represent a very promising treatment strategy. The use of HDACis as monotherapy has shown very positive pre-clinical results, but clinical trials have had only limited success. However, combinatorial regimens with other cancer drugs have shown synergistic effects both in pre-clinical and clinical studies. At the same time, these combinations have enhanced the efficacy, reduced the toxicity and tumor resistance to therapy. In this review, we will examine examples of HDACis used in combination with other cancer drugs and highlight the synergistic effects observed in recent preclinical and clinical studies.

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“…Our previous study has shown that SAHA and cladribine synergistically induce apoptosis in natural killer-large granular lymphocyte leukemia (NK-LGLL) [24]. Cladribine and SAHA, in combination with gemcitabine and busulfan, also provided synergistic cytotoxicity in lymphoma cell lines [25]. Stephen E. Spurgeon showed a phase 1/2 study, which using SAHA, cladribine, and rituximab in relapsed B-cell non-Hodgkin lymphoma (NHL) and previously untreated MCL resulted in a high complete response rate [26].…”

Section: Ivyspringmentioning

confidence: 99%

Cladribine Induces ATF4 Mediated Apoptosis and Synergizes with SAHA in Diffuse Large B-Cell Lymphoma Cells

Jiao

Sun

et al. 2020

Int. J. Med. Sci.

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Cladribine is a purine nucleoside analog used to treat B-cell chronic lymphocytic leukemia and hairy cell leukemia, also functions as an inhibitor of DNA synthesis to block the repair of the damaged DNA. The therapeutic role of cladribine against diffuse large B-cell lymphoma cells (DLBCL) is still undefined. In the present study, we demonstrated that cladribine inhibited cell proliferation and induced G1 phase arrest in human DLBCL cells. Furthermore, we showed that cladribine induced apoptosis by decreasing the expression of c-FLIPL and increasing the expression of DR4 and the cleaved form of caspase8. Cladribine also upregulated the expression of Bax, and downregulated the expression of Mcl-1 and Bcl-2 in a dose-dependent manner. It also activated endoplasmic reticulum (ER) stress, and ATF4 expression was required for cladribine induced apoptosis. Also, we showed that suberoylanilide hydroxamic acid (SAHA) enhanced the pro-apoptotic role of cladribine. Collectively, cladribine activated extrinsic and intrinsic apoptotic signaling pathways via stimulating ER stress signaling pathway and eliciting synergistic effect with SAHA in DLBCL cells.

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Cladribine, gemcitabine, busulfan, and SAHA combination as a potential pretransplant conditioning regimen for lymphomas: A preclinical study

Cited by 7 publications

References 31 publications

A novel conditioning regimen of chidamide, cladribine, gemcitabine, and busulfan in the autologous stem cell transplantation of aggressive T-cell lymphoma

A novel conditioning regimen of chidamide, cladribine, gemcitabine, and busulfan in the autologous stem cell transplantation of aggressive T-cell lymphoma

Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for Clinical Trials

Cladribine Induces ATF4 Mediated Apoptosis and Synergizes with SAHA in Diffuse Large B-Cell Lymphoma Cells

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