Targeting AKT Kinase in Hydroxytamoxifen-Resistant Breast Cancer Cells
More than 650,000 people die each year from breast cancer, making it a particularly significant disease worldwide. The development of about 70% of breast tumors depends on steroid hormones, namely, estrogens. Estrogens trigger signaling pathways that support tumor growth and progression. Hydroxytamo...
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MDPI AG
2023-03-01
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| Online Access: | https://www.mdpi.com/2673-9992/20/1/4 |
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| author | Alexander M. Scherbakov Fedor B. Bogdanov Alexandra L. Mikhaylova Olga E. Andreeva Diana I. Salnikova |
| author_facet | Alexander M. Scherbakov Fedor B. Bogdanov Alexandra L. Mikhaylova Olga E. Andreeva Diana I. Salnikova |
| author_sort | Alexander M. Scherbakov |
| collection | DOAJ |
| description | More than 650,000 people die each year from breast cancer, making it a particularly significant disease worldwide. The development of about 70% of breast tumors depends on steroid hormones, namely, estrogens. Estrogens trigger signaling pathways that support tumor growth and progression. Hydroxytamoxifen (HT) halting estrogen-induced tumor growth is among the most effective drugs in current anticancer therapy. The purpose of this work was to investigate approaches to overcome breast cancer cell resistance to hydroxytamoxifen. Cells with resistance to the antiestrogen hydroxytamoxifen were obtained by long-term incubation of parental MCF7 cells with this drug. Estrogen receptor α (ERα) expression and progesterone receptor (PR) expression were analyzed by immunoblotting. The resistant MCF7/HT cells were found not to lose ERα expression. These cells were found to have slightly reduced ERα activity when compared to parental MCF7 cells. The expression of PR, one of the ERα targets, was downregulated in hydroxytamoxifen-resistant cells. AKT kinase belongs to the PI3K/AKT/mTOR signaling pathway, and its activity is associated with resistance. Three types of AKT inhibitors were evaluated, including AKT inhibitor IV (6-(2-benzothiazolyl)-1-ethyl-2-[2-(methylphenylamino)ethenyl]-3-phenyl-1H-benzimidazolium, monoiodide), 10-DEBC (2-chloro-N,N-diethyl-10H-phenoxazine-10-butanamine, monohydrochloride), and luminespib (HSP90 inhibitor, 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide). All three compounds showed high antiproliferative activity against hydroxytamoxifen-resistant cells. The IC<sub>50</sub> value of 10-DEBC was 4.2 µM, and this was when the AKT inhibitor IV was more active with IC<sub>50</sub> value of 390 nM. The HSP90 inhibitor luminespib, which reduces AKT expression, showed the highest activity against parental and hydroxytamoxifen-resistant breast cancer cells, with IC<sub>50</sub> values of 14 and 18 nM, respectively. Thus, the hydroxytamoxifen-resistant cells were found to partially retain hormone signaling and to be sensitive to selective AKT inhibitors. The best effects were discovered for HSP90-AKT blocker luminespib, with an IC<sub>50</sub> value of about 20 nM. |
| first_indexed | 2024-03-11T02:05:55Z |
| format | Article |
| id | doaj.art-0a9f0323dcc1441dbefba31cac28dd06 |
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| language | English |
| last_indexed | 2024-03-11T02:05:55Z |
| publishDate | 2023-03-01 |
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| spelling | doaj.art-0a9f0323dcc1441dbefba31cac28dd062023-11-18T11:52:41ZengMDPI AGMedical Sciences Forum2673-99922023-03-01201410.3390/IECC2023-14224Targeting AKT Kinase in Hydroxytamoxifen-Resistant Breast Cancer CellsAlexander M. Scherbakov0Fedor B. Bogdanov1Alexandra L. Mikhaylova2Olga E. Andreeva3Diana I. Salnikova4N.N. Blokhin National Medical Research Center of Oncology, The Ministry of Health of the Russian Federation, Moscow 115522, RussiaN.N. Blokhin National Medical Research Center of Oncology, The Ministry of Health of the Russian Federation, Moscow 115522, RussiaN.N. Blokhin National Medical Research Center of Oncology, The Ministry of Health of the Russian Federation, Moscow 115522, RussiaN.N. Blokhin National Medical Research Center of Oncology, The Ministry of Health of the Russian Federation, Moscow 115522, RussiaN.N. Blokhin National Medical Research Center of Oncology, The Ministry of Health of the Russian Federation, Moscow 115522, RussiaMore than 650,000 people die each year from breast cancer, making it a particularly significant disease worldwide. The development of about 70% of breast tumors depends on steroid hormones, namely, estrogens. Estrogens trigger signaling pathways that support tumor growth and progression. Hydroxytamoxifen (HT) halting estrogen-induced tumor growth is among the most effective drugs in current anticancer therapy. The purpose of this work was to investigate approaches to overcome breast cancer cell resistance to hydroxytamoxifen. Cells with resistance to the antiestrogen hydroxytamoxifen were obtained by long-term incubation of parental MCF7 cells with this drug. Estrogen receptor α (ERα) expression and progesterone receptor (PR) expression were analyzed by immunoblotting. The resistant MCF7/HT cells were found not to lose ERα expression. These cells were found to have slightly reduced ERα activity when compared to parental MCF7 cells. The expression of PR, one of the ERα targets, was downregulated in hydroxytamoxifen-resistant cells. AKT kinase belongs to the PI3K/AKT/mTOR signaling pathway, and its activity is associated with resistance. Three types of AKT inhibitors were evaluated, including AKT inhibitor IV (6-(2-benzothiazolyl)-1-ethyl-2-[2-(methylphenylamino)ethenyl]-3-phenyl-1H-benzimidazolium, monoiodide), 10-DEBC (2-chloro-N,N-diethyl-10H-phenoxazine-10-butanamine, monohydrochloride), and luminespib (HSP90 inhibitor, 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-N-ethyl-4-[4-(4-morpholinylmethyl)phenyl]-3-isoxazolecarboxamide). All three compounds showed high antiproliferative activity against hydroxytamoxifen-resistant cells. The IC<sub>50</sub> value of 10-DEBC was 4.2 µM, and this was when the AKT inhibitor IV was more active with IC<sub>50</sub> value of 390 nM. The HSP90 inhibitor luminespib, which reduces AKT expression, showed the highest activity against parental and hydroxytamoxifen-resistant breast cancer cells, with IC<sub>50</sub> values of 14 and 18 nM, respectively. Thus, the hydroxytamoxifen-resistant cells were found to partially retain hormone signaling and to be sensitive to selective AKT inhibitors. The best effects were discovered for HSP90-AKT blocker luminespib, with an IC<sub>50</sub> value of about 20 nM.https://www.mdpi.com/2673-9992/20/1/4breast cancerAKT inhibitor10-DEBChydroxytamoxifenluminespibresistance |
| spellingShingle | Alexander M. Scherbakov Fedor B. Bogdanov Alexandra L. Mikhaylova Olga E. Andreeva Diana I. Salnikova Targeting AKT Kinase in Hydroxytamoxifen-Resistant Breast Cancer Cells Medical Sciences Forum breast cancer AKT inhibitor 10-DEBC hydroxytamoxifen luminespib resistance |
| title | Targeting AKT Kinase in Hydroxytamoxifen-Resistant Breast Cancer Cells |
| title_full | Targeting AKT Kinase in Hydroxytamoxifen-Resistant Breast Cancer Cells |
| title_fullStr | Targeting AKT Kinase in Hydroxytamoxifen-Resistant Breast Cancer Cells |
| title_full_unstemmed | Targeting AKT Kinase in Hydroxytamoxifen-Resistant Breast Cancer Cells |
| title_short | Targeting AKT Kinase in Hydroxytamoxifen-Resistant Breast Cancer Cells |
| title_sort | targeting akt kinase in hydroxytamoxifen resistant breast cancer cells |
| topic | breast cancer AKT inhibitor 10-DEBC hydroxytamoxifen luminespib resistance |
| url | https://www.mdpi.com/2673-9992/20/1/4 |
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