Retinoid/arsenic combination therapy of promyelocytic leukemia: induction of telomerase-dependent cell death

Tárkányi, Ilona; Dudognon, Charles; Hillion, Josette; Pendino, Frédéric; Lanotte, Michele; Aradi, J.; Ségal-Bendirdjian, Évelyne

doi:10.1038/sj.leu.2403923

Cited by 35 publications

(28 citation statements)

References 30 publications

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“…This effect is due to enhanced phosphorylation of RARa (53). Additionally, combination treatment with ATRA and ATO enhances the downregulation of telomerase expression as compared to treatment with one agent alone, thereby enhancing cell death (54). Importantly, the synergetic effects of combined ATRA and ATO treatment have also been shown in vivo.…”

Section: Synergetic Effects Of Atra and Ato In Aplmentioning

confidence: 74%

Molecular Mechanisms of the Antileukemia Activities of Retinoid and Arsenic

Nitto

Sawaki

2014

J Pharmacol Sci

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Abstract. Acute promyelocytic leukemia (APL) is characterized by the occurrence of translocations between chromosomes 15 and 17, resulting in generation of a fusion protein of promyelocytic leukemia (PML) and retinoid A receptor (RAR) a. APL cells are unable to differentiate into mature granulocytes since PML-RARa functions as a strong transcriptional repressor for a gene involved in granulocyte differentiation. All-trans retinoic acid (ATRA) is the first agent that has been developed to target specific disease-causing molecules, i.e., ATRA suppresses abnormal functions of oncogenic proteins. Moreover, ATRA facilitates the differentiation of APL cells toward mature granulocytes by changing epigenetic modifiers from corepressor complexes to co-activator complexes on target genes after binding to the ligand-binding domain at the RARa moiety of the PML-RARa oncoprotein. On the other hand, arsenic trioxide (ATO), another promising agent used to treat APL, directly binds to the PML moiety of the PML-RARa protein, causing oxidation and multimerization. ATO enhances the conjugation of small ubiquitin-like modifiers to PML-RARa, followed by ubiquitination and degradation, relieving the genes associated with granulocytic differentiation from suppressive restraint by the oncoprotein. Recent clinical studies have demonstrated that combination therapy with both ATRA and ATO is useful to achieve remission.

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Section: Synergetic Effects Of Atra and Ato In Aplmentioning

confidence: 74%

Molecular Mechanisms of the Antileukemia Activities of Retinoid and Arsenic

Nitto

Sawaki

2014

J Pharmacol Sci

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“…It is used not only in the monotherapy but also in combination with other compounds, i.a. retinoid acid, ascorbic acid and GM-CSF [17][18][19].The impact of ATO bases mainly on the inhibition of proliferation and introduction of cancer cells on the route of programmed cell death. Its apoptotic effect has been proved for many years, however scientists all over the world are still proposing its new mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Effect of arsenic trioxide (Trisenox) on actin organization in K-562 erythroleukemia cells.

Izdebska

Grzanka²,

Ostrowski³

et al. 2010

Folia Histochem Cytobiol.

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Actin is one of the cytoskeletal proteins that take part in many cellular processes. The aim of this study was to show the influence of Trisenox (arsenic trioxide), on the cytoplasmic and nuclear F-actin organization. Arsenic trioxide is the proapoptotic factor. Together with increasing doses, it caused the increase in the number of cells undergoing apoptosis. Under arsenic trioxide treatment, cytoplasmic and nuclear F-actin (polymerized form of G-actin) was found reorganized. It was transformed into granulated structures. In cytometer studies fluorescence intensity of cytoplasmic F-actin after ATO treatment decreasing urgently in comparison to control. The obtained results may suggest the involvement of F-actin in apoptosis, especially in chromatin reorganization.

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“…We have previously demonstrated the existence of distinct thresholds necessary for telomere shortening and cell death, which can vary depending on the targeted cancer cells. 20 It is likely that these thresholds apply also in case of patient cells explaining why despite significant hTERT repression induced by the RARa agonist alone no significant effect on telomere length was observed. Moreover, we cannot exclude that some destabilization of telomere structure may accompany hTERT (19) 81 (9) 63 (4) 52 (3) AML5 Pt 11 96 (10) 34 (9) 72 (0.1) 23 (4) CMML Pt 19 45 (19) 52 (19) 53 (14) 35 (19) CML Pt 12 63 (2) 98 (32) 64 (na) 38 (na) CML Pt 14 55 (36) 61 (15) 60 (15) 67 (na) CML Pt 15 12 (8) nd 98 (49) 18 (4) CML Pt 16 90 (1) 100 (38) 30 (11) 44 (18) CML Pt 17 13 (18) 10 (6) 24 (2) Retinoids target hTERT in myeloid leukemias F Pendino et al repression leading to such a rapid shortening in only 11 days.…”

Section: Retinoids Target Htert In Myeloid Leukemiasmentioning

confidence: 99%

Telomerase targeting by retinoids in cells from patients with myeloid leukemias of various subtypes, not only APL

et al. 2006

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Numerous strategies have been proposed to specifically inhibit telomerase (human telomerase reverse transcriptase (hTERT)) but to date only a few are clinically relevant in anticancer therapy. Recently, we have shown that long-term treatment with all-trans retinoic acid (ATRA), a compound clinically approved for differentiation therapy of acute promyelocytic leukemia (APL), represses hTERT in differentiation-resistant APL cell lines leading to telomere shortening and death. This signaling requires the co-activation of the retinoic acid receptor a (RARa) and the retinoic X receptor (RXR). In contrast to differentiationtherapy, which is only successful in this subtype of leukemia, the telomerase-targeted pathway could also be of use in non-APL. Here, we demonstrate that repression of hTERT occurs in fresh blasts cells from patients with myeloid leukemias of various subtypes exposed ex vivo to ATRA or synthetic retinoids. These results support the idea that, by hTERT targeting, retinoids can induce telomere shortening and cell death and their integration in therapy protocols for myeloid leukemias refractory to maturation should be considered. Leukemia (2006) IntroductionTelomerase is a ribonucleoprotein complex responsible for the maintenance of telomeres. Its activity is generally undetectable in normal somatic cells, while it is expressed in approximately 85% of the common cancers. Expression of the catalytic protein component of the telomerase complex, hTERT (human Telomerase Reverse Transcriptase) plays a fundamental role in cellular immortalization. Hematopoietic stem cells express telomerase, 1-3 but not at a sufficient level to fully maintain telomere length. It is acknowledged that a high level of telomerase activity is detected in acute myeloid leukemia (more than 10-fold compared to normal hematopoietic cells) and during progression of chronic myeloid leukemia (CML). [4][5][6][7][8] Telomere shortening has also been described associated with progression of myelodysplastic syndrome (MDS) to overt leukemia. 9,10 As most cancer cells are reliant on telomerase for their survival, it has become a promising target of anticancer therapy. Even though multiple strategies have been described to specifically inhibit telomerase in vitro, 11 most of them have not been tested yet in clinical trials or are not relevant because of their low efficacy and/or a high toxicity.Among myeloid leukemias, acute promyelocytic leukemia (APL) was found to be particularly sensitive to differentiation therapy using pharmacological doses of all-trans retinoic acid (ATRA), which induce remission of APL patients by stimulating differentiation of leukemic cells. [12][13][14] Recently, we identified a new maturation-independent pathway, by which ATRA exerts an antiproliferative activity through hTERT downregulation, leading to telomere shortening and cell death. [15][16][17] The significance and extension of this observation to malignancies resistant to retinoid-induced differentiation is currently unknown. Here, we questioned whether h...

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Retinoid/arsenic combination therapy of promyelocytic leukemia: induction of telomerase-dependent cell death

Cited by 35 publications

References 30 publications

Molecular Mechanisms of the Antileukemia Activities of Retinoid and Arsenic

Molecular Mechanisms of the Antileukemia Activities of Retinoid and Arsenic

Effect of arsenic trioxide (Trisenox) on actin organization in K-562 erythroleukemia cells.

Telomerase targeting by retinoids in cells from patients with myeloid leukemias of various subtypes, not only APL

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