Raloxifene Suppresses Tumor Growth and Metastasis in an Orthotopic Model of Castration-Resistant Prostate Cancer
Androgen receptor (AR)-castrate-resistant prostate cancer (CRPC) is an aggressive form of prostate cancer that does not have clinically approved targeted treatment options. To this end, the cytotoxic potential of raloxifene and the synthetic curcumin derivative 2,6-bis (pyridin-4-ylmethylene)-cycloh...
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| Format: | Article |
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MDPI AG
2022-04-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/10/4/853 |
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| author | Hannah Palmer Mhairi Nimick Aloran Mazumder Sebastien Taurin Zohaib Rana Rhonda J. Rosengren |
| author_facet | Hannah Palmer Mhairi Nimick Aloran Mazumder Sebastien Taurin Zohaib Rana Rhonda J. Rosengren |
| author_sort | Hannah Palmer |
| collection | DOAJ |
| description | Androgen receptor (AR)-castrate-resistant prostate cancer (CRPC) is an aggressive form of prostate cancer that does not have clinically approved targeted treatment options. To this end, the cytotoxic potential of raloxifene and the synthetic curcumin derivative 2,6-bis (pyridin-4-ylmethylene)-cyclohexanone (RL91) was examined in AR-(PC3 and DU145) cells and AR+ (LnCaP) CRPC cells. The results showed that both raloxifene and RL91 elicited significant cytotoxicity across three cell lines with the lowest EC<sub>50</sub> values in PC3 cells. Additionally, the two drugs were synergistically cytotoxic toward the PC3, DU-145 and LNCaP cell lines. To determine the effect of the drug combination in vivo, an orthotopic model of CRPC was used. Male mice were injected with PC3 prostate cancer cells and then treated with vehicle (5 mL/kg), raloxifene (8.5 mg/kg, po), RL91 (8.5 mg/kg, po) or a combination of raloxifene and RL91 for six weeks. Sham animals were subjected to the surgical procedure but were not implanted with PC3 cells. The results showed that raloxifene decreased tumor size and weight as well as metastasis to renal lymph nodes. However, combination treatment reversed the efficacy of raloxifene as tumor volume and metastasis returned to control levels. The results suggest that raloxifene has tumor suppressive and anti-metastatic effects and has potential for further clinical use in AR-CRPC. |
| first_indexed | 2024-03-09T11:07:24Z |
| format | Article |
| id | doaj.art-af40c00f01894d87b20e909f23539b10 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T11:07:24Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-af40c00f01894d87b20e909f23539b102023-12-01T00:54:21ZengMDPI AGBiomedicines2227-90592022-04-0110485310.3390/biomedicines10040853Raloxifene Suppresses Tumor Growth and Metastasis in an Orthotopic Model of Castration-Resistant Prostate CancerHannah Palmer0Mhairi Nimick1Aloran Mazumder2Sebastien Taurin3Zohaib Rana4Rhonda J. Rosengren5Department of Pharmacology and Toxicology, University of Otago, Dunedin 9016, New ZealandDepartment of Pharmacology and Toxicology, University of Otago, Dunedin 9016, New ZealandDepartment of Pharmacology and Toxicology, University of Otago, Dunedin 9016, New ZealandDepartment of Pharmacology and Toxicology, University of Otago, Dunedin 9016, New ZealandDepartment of Biochemistry, University of Otago, Dunedin 9016, New ZealandDepartment of Pharmacology and Toxicology, University of Otago, Dunedin 9016, New ZealandAndrogen receptor (AR)-castrate-resistant prostate cancer (CRPC) is an aggressive form of prostate cancer that does not have clinically approved targeted treatment options. To this end, the cytotoxic potential of raloxifene and the synthetic curcumin derivative 2,6-bis (pyridin-4-ylmethylene)-cyclohexanone (RL91) was examined in AR-(PC3 and DU145) cells and AR+ (LnCaP) CRPC cells. The results showed that both raloxifene and RL91 elicited significant cytotoxicity across three cell lines with the lowest EC<sub>50</sub> values in PC3 cells. Additionally, the two drugs were synergistically cytotoxic toward the PC3, DU-145 and LNCaP cell lines. To determine the effect of the drug combination in vivo, an orthotopic model of CRPC was used. Male mice were injected with PC3 prostate cancer cells and then treated with vehicle (5 mL/kg), raloxifene (8.5 mg/kg, po), RL91 (8.5 mg/kg, po) or a combination of raloxifene and RL91 for six weeks. Sham animals were subjected to the surgical procedure but were not implanted with PC3 cells. The results showed that raloxifene decreased tumor size and weight as well as metastasis to renal lymph nodes. However, combination treatment reversed the efficacy of raloxifene as tumor volume and metastasis returned to control levels. The results suggest that raloxifene has tumor suppressive and anti-metastatic effects and has potential for further clinical use in AR-CRPC.https://www.mdpi.com/2227-9059/10/4/853CRPCAR-prostate cancerraloxifenecurcumin derivativecombination therapyanti-cancer agent |
| spellingShingle | Hannah Palmer Mhairi Nimick Aloran Mazumder Sebastien Taurin Zohaib Rana Rhonda J. Rosengren Raloxifene Suppresses Tumor Growth and Metastasis in an Orthotopic Model of Castration-Resistant Prostate Cancer Biomedicines CRPC AR-prostate cancer raloxifene curcumin derivative combination therapy anti-cancer agent |
| title | Raloxifene Suppresses Tumor Growth and Metastasis in an Orthotopic Model of Castration-Resistant Prostate Cancer |
| title_full | Raloxifene Suppresses Tumor Growth and Metastasis in an Orthotopic Model of Castration-Resistant Prostate Cancer |
| title_fullStr | Raloxifene Suppresses Tumor Growth and Metastasis in an Orthotopic Model of Castration-Resistant Prostate Cancer |
| title_full_unstemmed | Raloxifene Suppresses Tumor Growth and Metastasis in an Orthotopic Model of Castration-Resistant Prostate Cancer |
| title_short | Raloxifene Suppresses Tumor Growth and Metastasis in an Orthotopic Model of Castration-Resistant Prostate Cancer |
| title_sort | raloxifene suppresses tumor growth and metastasis in an orthotopic model of castration resistant prostate cancer |
| topic | CRPC AR-prostate cancer raloxifene curcumin derivative combination therapy anti-cancer agent |
| url | https://www.mdpi.com/2227-9059/10/4/853 |
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