Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine
Elevated activation of the autophagy pathway is currently thought to be one of the survival mechanisms allowing therapy-resistant cancer cells to escape elimination, including for cytarabine (AraC)-resistant acute myeloid leukemia (AML) patients. Consequently, the use of autophagy inhibitors such as...
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MDPI AG
2021-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/5/2337 |
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| author | Nienke Visser Harm Jan Lourens Gerwin Huls Edwin Bremer Valerie R. Wiersma |
| author_facet | Nienke Visser Harm Jan Lourens Gerwin Huls Edwin Bremer Valerie R. Wiersma |
| author_sort | Nienke Visser |
| collection | DOAJ |
| description | Elevated activation of the autophagy pathway is currently thought to be one of the survival mechanisms allowing therapy-resistant cancer cells to escape elimination, including for cytarabine (AraC)-resistant acute myeloid leukemia (AML) patients. Consequently, the use of autophagy inhibitors such as chloroquine (CQ) is being explored for the re-sensitization of AraC-resistant cells. In our study, no difference in the activity of the autophagy pathway was detected when comparing AraC-Res AML cell lines to parental AraC-sensitive AML cell lines. Furthermore, treatment with autophagy inhibitors CQ, 3-Methyladenine (3-MA), and bafilomycin A1 (BafA1) did not re-sensitize AraC-Res AML cell lines to AraC treatment. However, in parental AraC-sensitive AML cells, treatment with AraC did activate autophagy and, correspondingly, combination of AraC with autophagy inhibitors strongly reduced cell viability. Notably, the combination of these drugs also yielded the highest level of cell death in a panel of patient-derived AML samples even though not being additive. Furthermore, there was no difference in the cytotoxic effect of autophagy inhibition during AraC treatment in matched de novo and relapse samples with differential sensitivity to AraC. Thus, inhibition of autophagy may improve AraC efficacy in AML patients, but does not seem warranted for the treatment of AML patients that have relapsed with AraC-resistant disease. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T00:30:24Z |
| publishDate | 2021-02-01 |
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| spelling | doaj.art-5921a5ebb62f4e66960a2d8c0cde240f2023-12-11T18:34:52ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01225233710.3390/ijms22052337Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to CytarabineNienke Visser0Harm Jan Lourens1Gerwin Huls2Edwin Bremer3Valerie R. Wiersma4Department of Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The NetherlandsElevated activation of the autophagy pathway is currently thought to be one of the survival mechanisms allowing therapy-resistant cancer cells to escape elimination, including for cytarabine (AraC)-resistant acute myeloid leukemia (AML) patients. Consequently, the use of autophagy inhibitors such as chloroquine (CQ) is being explored for the re-sensitization of AraC-resistant cells. In our study, no difference in the activity of the autophagy pathway was detected when comparing AraC-Res AML cell lines to parental AraC-sensitive AML cell lines. Furthermore, treatment with autophagy inhibitors CQ, 3-Methyladenine (3-MA), and bafilomycin A1 (BafA1) did not re-sensitize AraC-Res AML cell lines to AraC treatment. However, in parental AraC-sensitive AML cells, treatment with AraC did activate autophagy and, correspondingly, combination of AraC with autophagy inhibitors strongly reduced cell viability. Notably, the combination of these drugs also yielded the highest level of cell death in a panel of patient-derived AML samples even though not being additive. Furthermore, there was no difference in the cytotoxic effect of autophagy inhibition during AraC treatment in matched de novo and relapse samples with differential sensitivity to AraC. Thus, inhibition of autophagy may improve AraC efficacy in AML patients, but does not seem warranted for the treatment of AML patients that have relapsed with AraC-resistant disease.https://www.mdpi.com/1422-0067/22/5/2337AMLautophagycytarabinetherapy resistanceautophagy inhibitorschloroquine |
| spellingShingle | Nienke Visser Harm Jan Lourens Gerwin Huls Edwin Bremer Valerie R. Wiersma Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine International Journal of Molecular Sciences AML autophagy cytarabine therapy resistance autophagy inhibitors chloroquine |
| title | Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine |
| title_full | Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine |
| title_fullStr | Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine |
| title_full_unstemmed | Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine |
| title_short | Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine |
| title_sort | inhibition of autophagy does not re sensitize acute myeloid leukemia cells resistant to cytarabine |
| topic | AML autophagy cytarabine therapy resistance autophagy inhibitors chloroquine |
| url | https://www.mdpi.com/1422-0067/22/5/2337 |
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