Dual inhibition of AKT and autophagy sensitizes triple negative breast cancer cells to carboplatin
Triple-negative breast cancer (TNBC) exhibits the highest recurrence and mortality rates among breast cancer subtypes. Approximately one million TNBC cases are diagnosed worldwide annually. Current clinical treatments, primarily chemotherapy regimens based on paclitaxel and anthracycline, are associ...
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| Language: | English |
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Elsevier
2025-08-01
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| Series: | Translational Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523325001652 |
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| author | Jun-zhen Zhou Jing-ya Wen Xin-wen Xu Na Zhao Jing-jing Tang Ye-rui Xiao Le-yang Xiang Yue Jiang Jian-wei jiang Hong Hong Qing Zhang |
| author_facet | Jun-zhen Zhou Jing-ya Wen Xin-wen Xu Na Zhao Jing-jing Tang Ye-rui Xiao Le-yang Xiang Yue Jiang Jian-wei jiang Hong Hong Qing Zhang |
| author_sort | Jun-zhen Zhou |
| collection | DOAJ |
| description | Triple-negative breast cancer (TNBC) exhibits the highest recurrence and mortality rates among breast cancer subtypes. Approximately one million TNBC cases are diagnosed worldwide annually. Current clinical treatments, primarily chemotherapy regimens based on paclitaxel and anthracycline, are associated with high recurrence rates and low overall survival rates. Platinum drugs, introduced for TNBC treatment, demonstrated a positive effect; however, their high-dose administration inevitably results in toxic side effects and drug resistance. Therefore, identifying agents that sensitize patients to platinum-based therapies is critical. Analysis of the TCGA database revealed that AKT1 and autophagy are activated in breast cancer, playing crucial roles in malignant behavior. Further investigation demonstrated that CBP activates the AKT pathway in MDA-MB-231 cells, while its combination with LY294002 or Triciribine (inhibitors of the PI3K/AKT pathway), suppresses cell proliferation. However, this combination also activates autophagy, a protective mechanism. Inhibition of autophagy with CQ or Baf A1 further increased the proliferation-inhibitory effects of CBP in MDA-MB-231 cells. Notably, the sesquiterpene lactone EM-2 extracted from Elephantopus mollis H.B.K., significantly inhibited both the AKT and autophagy pathways in TNBC cells, demonstrating superior cellular inhibitory effects compared with other AKT or autophagy inhibitors combined with CBP. When CBP was combined with EM-2, cell survival decreased by approximately 36 % compared with CBP monotherapy, while the apoptosis rate increased by 22.8 % after 48 h. The combination of CBP and EM2 also produced the greatest tumor shrinkage in vivo. Interestingly, the CBP (3 mg/kg) + EM-2 (6 mg/kg) group achieved the same tumor shrinkage, with only one-fifth the amount of CBP compared with the CBP (16 mg/kg) monotherapy group. In other words, low doses of EM-2 combined with CBP produced the same anti-tumor effects as high-dose CBP alone. These findings provide a novel strategy for the treatment of CBP using dual AKT and autophagy inhibitors, highlighting potential clinical applications. |
| format | Article |
| id | doaj-art-4232bd090b654ef7a072cb3242858e26 |
| institution | DOAJ |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-4232bd090b654ef7a072cb3242858e262025-08-20T03:20:03ZengElsevierTranslational Oncology1936-52332025-08-015810243410.1016/j.tranon.2025.102434Dual inhibition of AKT and autophagy sensitizes triple negative breast cancer cells to carboplatinJun-zhen Zhou0Jing-ya Wen1Xin-wen Xu2Na Zhao3Jing-jing Tang4Ye-rui Xiao5Le-yang Xiang6Yue Jiang7Jian-wei jiang8Hong Hong9Qing Zhang10Department of Breast Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, ChinaDepartment of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, ChinaDepartment of Breast Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, China; Department of Breast Surgery, Foshan Second People’s hospital, Foshan, Guangdong 52800, ChinaDepartment of Biochemistry, Basic Medical College, Jinan University, Guangzhou 510632, ChinaDepartment of Breast Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, China; Department of Breast and Thyroid Surgery, the Central Hospital of Yongzhou, Yongzhou, Hunan 425000, ChinaDepartment of Stomatology, Stomatological Medical College, Jinan University, Guangzhou, Guangdong 510632, ChinaDepartment of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, ChinaDepartment of Thyroid and Breast Surgery, Shunde Hospital of Jinan University, Foshan, Guangdong 528303, ChinaDepartment of Biochemistry, Basic Medical College, Jinan University, Guangzhou 510632, China; Corresponding authors.Department of Breast Surgery, The Hospital of eastern Dongguan, Dongguan, Guangdong 523560, China; Corresponding authors.Department of Breast Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, China; Corresponding authors.Triple-negative breast cancer (TNBC) exhibits the highest recurrence and mortality rates among breast cancer subtypes. Approximately one million TNBC cases are diagnosed worldwide annually. Current clinical treatments, primarily chemotherapy regimens based on paclitaxel and anthracycline, are associated with high recurrence rates and low overall survival rates. Platinum drugs, introduced for TNBC treatment, demonstrated a positive effect; however, their high-dose administration inevitably results in toxic side effects and drug resistance. Therefore, identifying agents that sensitize patients to platinum-based therapies is critical. Analysis of the TCGA database revealed that AKT1 and autophagy are activated in breast cancer, playing crucial roles in malignant behavior. Further investigation demonstrated that CBP activates the AKT pathway in MDA-MB-231 cells, while its combination with LY294002 or Triciribine (inhibitors of the PI3K/AKT pathway), suppresses cell proliferation. However, this combination also activates autophagy, a protective mechanism. Inhibition of autophagy with CQ or Baf A1 further increased the proliferation-inhibitory effects of CBP in MDA-MB-231 cells. Notably, the sesquiterpene lactone EM-2 extracted from Elephantopus mollis H.B.K., significantly inhibited both the AKT and autophagy pathways in TNBC cells, demonstrating superior cellular inhibitory effects compared with other AKT or autophagy inhibitors combined with CBP. When CBP was combined with EM-2, cell survival decreased by approximately 36 % compared with CBP monotherapy, while the apoptosis rate increased by 22.8 % after 48 h. The combination of CBP and EM2 also produced the greatest tumor shrinkage in vivo. Interestingly, the CBP (3 mg/kg) + EM-2 (6 mg/kg) group achieved the same tumor shrinkage, with only one-fifth the amount of CBP compared with the CBP (16 mg/kg) monotherapy group. In other words, low doses of EM-2 combined with CBP produced the same anti-tumor effects as high-dose CBP alone. These findings provide a novel strategy for the treatment of CBP using dual AKT and autophagy inhibitors, highlighting potential clinical applications.http://www.sciencedirect.com/science/article/pii/S1936523325001652EM-2Breast cancerCarboplatinAutophagyAKT |
| spellingShingle | Jun-zhen Zhou Jing-ya Wen Xin-wen Xu Na Zhao Jing-jing Tang Ye-rui Xiao Le-yang Xiang Yue Jiang Jian-wei jiang Hong Hong Qing Zhang Dual inhibition of AKT and autophagy sensitizes triple negative breast cancer cells to carboplatin Translational Oncology EM-2 Breast cancer Carboplatin Autophagy AKT |
| title | Dual inhibition of AKT and autophagy sensitizes triple negative breast cancer cells to carboplatin |
| title_full | Dual inhibition of AKT and autophagy sensitizes triple negative breast cancer cells to carboplatin |
| title_fullStr | Dual inhibition of AKT and autophagy sensitizes triple negative breast cancer cells to carboplatin |
| title_full_unstemmed | Dual inhibition of AKT and autophagy sensitizes triple negative breast cancer cells to carboplatin |
| title_short | Dual inhibition of AKT and autophagy sensitizes triple negative breast cancer cells to carboplatin |
| title_sort | dual inhibition of akt and autophagy sensitizes triple negative breast cancer cells to carboplatin |
| topic | EM-2 Breast cancer Carboplatin Autophagy AKT |
| url | http://www.sciencedirect.com/science/article/pii/S1936523325001652 |
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