Epigenetic drug combination overcomes osteoblast-induced chemoprotection in pediatric acute lymphoid leukemia

Quagliano, Anthony; Gopalakrishnapillai, Anilkumar; Barwe, Sonali P.

doi:10.1016/j.leukres.2017.01.030

Cited by 10 publications

(10 citation statements)

References 29 publications

(33 reference statements)

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“…To date, clinical trials with AZA have not been implemented in ALL. In vitro, AZA in combination with histone deacetylase inhibitor Panobinostat was reported to induce synergistic antiproliferative effects in ALL cell lines [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Decitabine demonstrates antileukemic activity in B cell precursor acute lymphoblastic leukemia with MLL rearrangements

et al. 2018

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BackgroundPromotor hypermethylation of CpG islands is common in B cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed lineage leukemia (MLL) gene rearrangements. Hypomethylating agents (HMA) such as azacitidine (AZA) and decitabine (DEC) reduce DNA hypermethylation by incorporation into DNA and were successfully introduced into the clinic for the treatment of myeloid neoplasias.MethodsHere, we investigated whether HMA induce comparable biological effects in MLL-positive BCP-ALL. Further, efficacy of HMA and concomitant application of cytostatic drugs (cytarabine and doxorubicin) were evaluated on established SEM and RS4;11 cell lines. In addition, promising approaches were studied on BCP-ALL cell line- and patient-derived xenograft models.ResultsIn general, DEC effects were stronger compared to AZA on MLL-positive BCP-ALL cells. DEC significantly reduced proliferation by induction of cell cycle arrest in G0/G1 phase and apoptosis. Most sensitive to HMA were SEM cells which are characterized by a fast cell doubling time. The combination of low-dose HMA and conventional cytostatic agents revealed a heterogeneous response pattern. The strongest antiproliferative effects were observed when ALL cells were simultaneously exposed to HMA and cytostatic drugs. Most potent synergistic effects of HMA were induced with cytarabine. Finally, the therapeutic potential of DEC was evaluated on BCP-ALL xenograft models. DEC significantly delayed leukemic proliferation in xenograft models as demonstrated longitudinally by non-invasive bioluminescence as well as 18F-FDG-PET/CT imaging. Unexpectedly, in vivo concomitant application of DEC and cytarabine did not enhance the antiproliferative effect compared to DEC monotherapy.ConclusionsOur data reveal that DEC is active in MLL-positive BCP-ALL and warrant clinical evaluation.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0607-3) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Decitabine demonstrates antileukemic activity in B cell precursor acute lymphoblastic leukemia with MLL rearrangements

et al. 2018

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“…In chemoresistant acute lymphoblastic leukemia, the interaction of cells within the bone marrow microenvironment is reported to be facilitated by epigenetic modifiers. Inhibition of these interactions using DNMT inhibitor azacitidine and HDACi panobinostat reportedly chemosensitizes these cells [ 144 ].…”

Section: The Role Of Tumor Microenvironment In Supporting Tumor Progr...mentioning

confidence: 99%

The paradigm of drug resistance in cancer: an epigenetic perspective

et al. 2022

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Innate and acquired resistance towards the conventional therapeutic regimen imposes a significant challenge for the successful management of cancer for decades. In patients with advanced carcinomas, acquisition of drug resistance often leads to tumor recurrence and poor prognosis after the first therapeutic cycle. In this context, cancer stem cells (CSCs) are considered as the prime drivers of therapy resistance in cancer due to their ‘non-targetable’ nature. Drug resistance in cancer is immensely influenced by different properties of CSCs such as epithelial-to-mesenchymal transition (EMT), a profound expression of drug efflux pump genes, detoxification genes, quiescence, and evasion of apoptosis, has been highlighted in this review article. The crucial epigenetic alterations that are intricately associated with regulating different mechanisms of drug resistance, have been discussed thoroughly. Additionally, special attention is drawn towards the epigenetic mechanisms behind the interaction between the cancer cells and their microenvironment which assists in tumor progression and therapy resistance. Finally, we have provided a cumulative overview of the alternative treatment strategies and epigenome-modifying therapies that show the potential of sensitizing the resistant cells towards the conventional treatment strategies. Thus, this review summarizes the epigenetic and molecular background behind therapy resistance, the prime hindrance of present day anti-cancer therapies, and provides an account of the novel complementary epi-drug-based therapeutic strategies to combat drug resistance.

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“…Disruption of these interactions mobilizes cells from the bone marrow into the peripheral blood, thereby sensitizing them to therapy. In acute lymphoblastic leukemia (ALL), azacitidine (DNMTi) and panobinostat (HDACi) combined to disrupt cellular adhesion within the bone marrow microenvironment in ALL by decreasing the surface expression of the tetraspanin protein CD81, resulting in increased chemosensitivity ( 155 , 156 ).…”

Section: Epigenetic Drug-induced Sensitization Mechanismsmentioning

confidence: 99%

Understanding the Mechanisms by Which Epigenetic Modifiers Avert Therapy Resistance in Cancer

2020

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The development of resistance to anti-cancer therapeutics remains one of the core issues preventing the improvement of survival rates in cancer. Therapy resistance can arise in a multitude of ways, including the accumulation of epigenetic alterations in cancer cells. By remodeling DNA methylation patterns or modifying histone proteins during oncogenesis, cancer cells reorient their epigenomic landscapes in order to aggressively resist anti-cancer therapy. To combat these chemoresistant effects, epigenetic modifiers such as DNA hypomethylating agents, histone deacetylase inhibitors, histone demethylase inhibitors, along with others have been used. While these modifiers have achieved moderate success when used either alone or in combination with one another, the most positive outcomes were achieved when they were used in conjunction with conventional anti-cancer therapies. Epigenome modifying drugs have succeeded in sensitizing cancer cells to anti-cancer therapy via a variety of mechanisms: disrupting pro-survival/anti-apoptotic signaling, restoring cell cycle control and preventing DNA damage repair, suppressing immune system evasion, regulating altered metabolism, disengaging pro-survival microenvironmental interactions and increasing protein expression for targeted therapies. In this review, we explore different mechanisms by which epigenetic modifiers induce sensitivity to anti-cancer therapies and encourage the further identification of the specific genes involved with sensitization to facilitate development of clinical trials.

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Epigenetic drug combination overcomes osteoblast-induced chemoprotection in pediatric acute lymphoid leukemia

Cited by 10 publications

References 29 publications

Decitabine demonstrates antileukemic activity in B cell precursor acute lymphoblastic leukemia with MLL rearrangements

Decitabine demonstrates antileukemic activity in B cell precursor acute lymphoblastic leukemia with MLL rearrangements

The paradigm of drug resistance in cancer: an epigenetic perspective

Understanding the Mechanisms by Which Epigenetic Modifiers Avert Therapy Resistance in Cancer

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