Combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator AMP-activated kinase
Abstract Background Current chemotherapy for castration-resistant prostate cancer is established on taxane-based compounds like docetaxel. However, eventually, the development of toxic side effects and resistance limits the therapeutic benefit being the major concern in the treatment of prostate can...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-03-01
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| Series: | Cancer Cell International |
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| Online Access: | http://link.springer.com/article/10.1186/s12935-019-0769-2 |
| _version_ | 1818132363012472832 |
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| author | Belén G. Sánchez Alicia Bort Pedro A. Mateos-Gómez Nieves Rodríguez-Henche Inés Díaz-Laviada |
| author_facet | Belén G. Sánchez Alicia Bort Pedro A. Mateos-Gómez Nieves Rodríguez-Henche Inés Díaz-Laviada |
| author_sort | Belén G. Sánchez |
| collection | DOAJ |
| description | Abstract Background Current chemotherapy for castration-resistant prostate cancer is established on taxane-based compounds like docetaxel. However, eventually, the development of toxic side effects and resistance limits the therapeutic benefit being the major concern in the treatment of prostate cancer. Combination therapies in many cases, enhance drug efficacy and delay the appearance of undesired effects, representing an important option for the treatment of castration-resistant prostate cancer. In this study, we tested the efficacy of the combination of docetaxel and capsaicin, the pungent ingredient of hot chili peppers, on prostate cancer cells proliferation. Methods Prostate cancer LNCaP and PC3 cell lines were used in this study. Levels of total and phosphorylated forms of Akt, mTOR, S6, LKB1, AMPK and ACC were determined by Western blot. AMPK, LKB1 and Akt knock down was performed by siRNA. PTEN was overexpressed by transient transfection with plasmids. Xenograft prostate tumors were induced in nude mice and treatments (docetaxel and capsaicin) were administered intraperitoneally. Statistical analyses were performed with GraphPad software. Combination index was calculated with Compusyn software. Results Docetaxel and capsaicin synergistically inhibited the growth of LNCaP and PC3 cells, with a combination index lower than 1 for most of the combinations tested. Co-treatment with docetaxel and capsaicin notably decreased Akt and its downstream targets mTOR and S6 phosphorylation. Overexpression of PTEN phosphatase abrogated the synergistic antiproliferative effect of docetaxel and capsaicin. The combined treatment also increased the phosphorylation of AMP-activated kinase (AMPK) and the phosphorylation of its substrate ACC. In addition, pharmacological inhibition of AMPK with dorsomorphin (compound C) as well as knock down by siRNA of AMPK or its upstream kinase LKB1, abolished the synergy of docetaxel and capsaicin. Mechanistically, we showed that the synergistic anti-proliferative effect may be attributed to two independent effects: Inhibition of the PI3K/Akt/mTOR signaling pathway by one side, and AMPK activation by the other. In vivo experiments confirmed the synergistic effects of docetaxel and capsaicin in reducing the tumor growth of PC3 cells. Conclusion Combination of docetaxel and capsaicin represents a therapeutically relevant approach for the treatment of Prostate Cancer. |
| first_indexed | 2024-12-11T08:35:38Z |
| format | Article |
| id | doaj.art-d20b7b4fc2d54d669631da9dc77519d5 |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-12-11T08:35:38Z |
| publishDate | 2019-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-d20b7b4fc2d54d669631da9dc77519d52022-12-22T01:14:21ZengBMCCancer Cell International1475-28672019-03-0119111410.1186/s12935-019-0769-2Combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator AMP-activated kinaseBelén G. Sánchez0Alicia Bort1Pedro A. Mateos-Gómez2Nieves Rodríguez-Henche3Inés Díaz-Laviada4Department of Systems Biology, Biochemistry and Molecular Biology Unit, School of Medicine and Health Sciences, Alcala University, Alcalá de HenaresDepartment of Systems Biology, Biochemistry and Molecular Biology Unit, School of Medicine and Health Sciences, Alcala University, Alcalá de HenaresDepartment of Systems Biology, Biochemistry and Molecular Biology Unit, School of Medicine and Health Sciences, Alcala University, Alcalá de HenaresDepartment of Systems Biology, Biochemistry and Molecular Biology Unit, School of Medicine and Health Sciences, Alcala University, Alcalá de HenaresDepartment of Systems Biology, Biochemistry and Molecular Biology Unit, School of Medicine and Health Sciences, Alcala University, Alcalá de HenaresAbstract Background Current chemotherapy for castration-resistant prostate cancer is established on taxane-based compounds like docetaxel. However, eventually, the development of toxic side effects and resistance limits the therapeutic benefit being the major concern in the treatment of prostate cancer. Combination therapies in many cases, enhance drug efficacy and delay the appearance of undesired effects, representing an important option for the treatment of castration-resistant prostate cancer. In this study, we tested the efficacy of the combination of docetaxel and capsaicin, the pungent ingredient of hot chili peppers, on prostate cancer cells proliferation. Methods Prostate cancer LNCaP and PC3 cell lines were used in this study. Levels of total and phosphorylated forms of Akt, mTOR, S6, LKB1, AMPK and ACC were determined by Western blot. AMPK, LKB1 and Akt knock down was performed by siRNA. PTEN was overexpressed by transient transfection with plasmids. Xenograft prostate tumors were induced in nude mice and treatments (docetaxel and capsaicin) were administered intraperitoneally. Statistical analyses were performed with GraphPad software. Combination index was calculated with Compusyn software. Results Docetaxel and capsaicin synergistically inhibited the growth of LNCaP and PC3 cells, with a combination index lower than 1 for most of the combinations tested. Co-treatment with docetaxel and capsaicin notably decreased Akt and its downstream targets mTOR and S6 phosphorylation. Overexpression of PTEN phosphatase abrogated the synergistic antiproliferative effect of docetaxel and capsaicin. The combined treatment also increased the phosphorylation of AMP-activated kinase (AMPK) and the phosphorylation of its substrate ACC. In addition, pharmacological inhibition of AMPK with dorsomorphin (compound C) as well as knock down by siRNA of AMPK or its upstream kinase LKB1, abolished the synergy of docetaxel and capsaicin. Mechanistically, we showed that the synergistic anti-proliferative effect may be attributed to two independent effects: Inhibition of the PI3K/Akt/mTOR signaling pathway by one side, and AMPK activation by the other. In vivo experiments confirmed the synergistic effects of docetaxel and capsaicin in reducing the tumor growth of PC3 cells. Conclusion Combination of docetaxel and capsaicin represents a therapeutically relevant approach for the treatment of Prostate Cancer.http://link.springer.com/article/10.1186/s12935-019-0769-2DocetaxelCapsaicinAMPKPC3 cellsLNCaP cellsProstate cancer |
| spellingShingle | Belén G. Sánchez Alicia Bort Pedro A. Mateos-Gómez Nieves Rodríguez-Henche Inés Díaz-Laviada Combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator AMP-activated kinase Cancer Cell International Docetaxel Capsaicin AMPK PC3 cells LNCaP cells Prostate cancer |
| title | Combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator AMP-activated kinase |
| title_full | Combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator AMP-activated kinase |
| title_fullStr | Combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator AMP-activated kinase |
| title_full_unstemmed | Combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator AMP-activated kinase |
| title_short | Combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator AMP-activated kinase |
| title_sort | combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator amp activated kinase |
| topic | Docetaxel Capsaicin AMPK PC3 cells LNCaP cells Prostate cancer |
| url | http://link.springer.com/article/10.1186/s12935-019-0769-2 |
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