Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer
Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors are efficacious in treating platinum-sensitive ovarian cancer (OC), but demonstrate limited efficiency in patients with platinum-resistant OC. Thus, further investigations into combined strategies that enhance the response to PARP inhibitors (P...
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| Format: | Article |
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Nature Publishing Group
2022-09-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05257-y |
| _version_ | 1811253636854972416 |
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| author | Sangsang Tang Yuanming Shen Xinyi Wei Zhangjin Shen Weiguo Lu Junfen Xu |
| author_facet | Sangsang Tang Yuanming Shen Xinyi Wei Zhangjin Shen Weiguo Lu Junfen Xu |
| author_sort | Sangsang Tang |
| collection | DOAJ |
| description | Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors are efficacious in treating platinum-sensitive ovarian cancer (OC), but demonstrate limited efficiency in patients with platinum-resistant OC. Thus, further investigations into combined strategies that enhance the response to PARP inhibitors (PARPi) in platinum-resistant OC are required. The present study aimed to investigate the combined therapy of arsenic trioxide (ATO) with olaparib, a common PARPi, and determine how this synergistic cytotoxicity works in platinum-resistant OC cells. Functional assays demonstrated that the combined treatment of olaparib with ATO significantly suppressed cell proliferation and colony formation, and enhanced DNA damage as well as cell apoptosis in A2780-CIS and SKOV3-CIS cell lines. Results of the present study also demonstrated that a combination of olaparib with ATO increased lipid peroxidation and eventually triggered ferroptosis. Consistently, the combined treatment synergistically suppressed tumor growth in mice xenograft models. Mechanistically, ATO in combination with olaparib activated the AMPK α pathway and suppressed the expression levels of stearoyl-CoA desaturase 1 (SCD1). Collectively, results of the present study demonstrated that treatment with ATO enhanced the effects of olaparib in platinum-resistant OC. |
| first_indexed | 2024-04-12T16:53:57Z |
| format | Article |
| id | doaj.art-7d21a15fc0d747189920e26c5a19a03b |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-12T16:53:57Z |
| publishDate | 2022-09-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death and Disease |
| spelling | doaj.art-7d21a15fc0d747189920e26c5a19a03b2022-12-22T03:24:18ZengNature Publishing GroupCell Death and Disease2041-48892022-09-0113911410.1038/s41419-022-05257-yOlaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancerSangsang Tang0Yuanming Shen1Xinyi Wei2Zhangjin Shen3Weiguo Lu4Junfen Xu5Women’s Reproductive Health Laboratory of Zhejiang Province, Women’s Hospital, Zhejiang University School of MedicineDepartment of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of MedicineWomen’s Reproductive Health Laboratory of Zhejiang Province, Women’s Hospital, Zhejiang University School of MedicineWomen’s Reproductive Health Laboratory of Zhejiang Province, Women’s Hospital, Zhejiang University School of MedicineDepartment of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of MedicineDepartment of Gynecologic Oncology, Women’s Hospital, Zhejiang University School of MedicineAbstract Poly (ADP-ribose) polymerase (PARP) inhibitors are efficacious in treating platinum-sensitive ovarian cancer (OC), but demonstrate limited efficiency in patients with platinum-resistant OC. Thus, further investigations into combined strategies that enhance the response to PARP inhibitors (PARPi) in platinum-resistant OC are required. The present study aimed to investigate the combined therapy of arsenic trioxide (ATO) with olaparib, a common PARPi, and determine how this synergistic cytotoxicity works in platinum-resistant OC cells. Functional assays demonstrated that the combined treatment of olaparib with ATO significantly suppressed cell proliferation and colony formation, and enhanced DNA damage as well as cell apoptosis in A2780-CIS and SKOV3-CIS cell lines. Results of the present study also demonstrated that a combination of olaparib with ATO increased lipid peroxidation and eventually triggered ferroptosis. Consistently, the combined treatment synergistically suppressed tumor growth in mice xenograft models. Mechanistically, ATO in combination with olaparib activated the AMPK α pathway and suppressed the expression levels of stearoyl-CoA desaturase 1 (SCD1). Collectively, results of the present study demonstrated that treatment with ATO enhanced the effects of olaparib in platinum-resistant OC.https://doi.org/10.1038/s41419-022-05257-y |
| spellingShingle | Sangsang Tang Yuanming Shen Xinyi Wei Zhangjin Shen Weiguo Lu Junfen Xu Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer Cell Death and Disease |
| title | Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer |
| title_full | Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer |
| title_fullStr | Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer |
| title_full_unstemmed | Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer |
| title_short | Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer |
| title_sort | olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum resistant ovarian cancer |
| url | https://doi.org/10.1038/s41419-022-05257-y |
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