The anti-malarial drug chloroquine sensitizes oncogenic NOTCH1 driven human T-ALL to γ-secretase inhibition

Hounjet, Judith; Habets, R.; Schaaf, Marco B.E.; Hendrickx, Tessa C.; Barbeau, L.; Yahyanejad, Sanaz; Rouschop, Kasper M.A.; Groot, Arjan J.; Vooijs, Marc

doi:10.1038/s41388-019-0802-x

Cited by 25 publications

(27 citation statements)

References 55 publications

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“…While these innovative approaches are yet to be translated into clinical practice, targeting Notch trafficking is within reach. For example, chloroquine, a well-known 4-aminoquinoline antimalarial drug, interferes with intracellular trafficking and processing of oncogenic NOTCH1 [ 166 ]. Due to the narrow therapeutic index, it is unlikely that this drug will affect highly proliferating cells as a single drug, but it would be promising to use it in combination with standard chemotherapy agents.…”

Section: Discussionmentioning

confidence: 99%

“…The association of two potential anti-NOTCH agents has more rarely been attempted, given the risk of increased toxicity. Nevertheless, in a recent work, chloroquine (CQ), an autophagy inhibitor with known anti-cancer activity [ 166 , 215 ], enhanced the effect of GSI in PTEN wild-type T-ALL cell lines [ 166 ]. CQ reduces N-TM expression by altering the endosome-recycling of the protein.…”

Section: Improving the Gs Complex Inhibition Strategymentioning

confidence: 99%

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Targeting Notch Trafficking and Processing in Cancers

Pagliaro

Sissi

Roti

2020

Cells

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The Notch family comprises a group of four ligand-dependent receptors that control evolutionarily conserved developmental and homeostatic processes and transmit signals to the microenvironment. NOTCH undergoes remodeling, maturation, and trafficking in a series of post-translational events, including glycosylation, ubiquitination, and endocytosis. The regulatory modifications occurring in the endoplasmic reticulum/Golgi precede the intramembrane γ-secretase proteolysis and the transfer of active NOTCH to the nucleus. Hence, NOTCH proteins coexist in different subcellular compartments and undergo continuous relocation. Various factors, including ion concentration, enzymatic activity, and co-regulatory elements control Notch trafficking. Interfering with these regulatory mechanisms represents an innovative therapeutic way to bar oncogenic Notch signaling. In this review, we briefly summarize the role of Notch signaling in cancer and describe the protein modifications required for NOTCH to relocate across different subcellular compartments. We focus on the functional relationship between these modifications and the corresponding therapeutic options, and our findings could support the development of trafficking modulators as a potential alternative to the well-known γ-secretase inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Improving the Gs Complex Inhibition Strategymentioning

confidence: 99%

Targeting Notch Trafficking and Processing in Cancers

Pagliaro

Sissi

Roti

2020

Cells

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“…Combining GSI with other agents that can trigger cell death may be an alternative option to treatment of NOTCH1-mutant T-ALL [26,27]. Chloroquine (CQ) can increase the accumulation of reactive oxygen species in T-ALL, activate DNA damage, enhance GSI-induced cell cycle arrest in T-ALL, and interfere with ligand-independent NOTCH1 transportation and localization [28]. In addition, it can also reduce the concentration of GSI with less side effects [28].…”

Section: γ-Secretase Inhibitors (Gsis)mentioning

confidence: 99%

“…Chloroquine (CQ) can increase the accumulation of reactive oxygen species in T-ALL, activate DNA damage, enhance GSI-induced cell cycle arrest in T-ALL, and interfere with ligand-independent NOTCH1 transportation and localization [28]. In addition, it can also reduce the concentration of GSI with less side effects [28]. The combination therapy of GSIs and CQ showed excellent synergistic effect in vitro on T-ALL cell line [28].…”

Section: γ-Secretase Inhibitors (Gsis)mentioning

confidence: 99%

“…In addition, it can also reduce the concentration of GSI with less side effects [28]. The combination therapy of GSIs and CQ showed excellent synergistic effect in vitro on T-ALL cell line [28]. Because there is PI3K/mTOR pathway activation in T-ALL [29], some researchers have conducted experiments using GSI and mTOR inhibitor rapamycin in mouse model [30].…”

Section: γ-Secretase Inhibitors (Gsis)mentioning

confidence: 99%

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Advances of target therapy on NOTCH1 signaling pathway in T-cell acute lymphoblastic leukemia

Zheng

Wang

et al. 2020

Exp Hematol Oncol

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T-cell acute lymphoblastic leukemia (T-ALL) is one of the hematological malignancies. With the applications of chemotherapy regimens and allogeneic hematopoietic stem cell transplantation, the cure rate of T-ALL has been significantly improved. However, patients with relapsed and refractory T-ALL still lack effective treatment options. Gene mutations play an important role in T-ALL. The NOTCH1 gene mutation is the important one among these genetic mutations. Since the mutation of NOTCH1 gene is considered as a driving oncogene in T-ALL, targeting the NOTCH1 signaling patheway may be an effective option to overcome relapsed and refractory T-ALL. This review mainly summarizes the recent research advances of targeting on NOTCH1 signaling pathway in T-ALL.

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