Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells
Anticancer activities of plant polyphenols have been demonstrated in various models of neoplasia. However, evidence obtained in numerous in vitro studies indicates that proliferation arrest and/or killing of cancer cells require quite high micromolar concentrations of polyphenols that are difficult...
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MDPI AG
2021-10-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/10/10/1591 |
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| author | Saniya Ossikbayeva Marina Khanin Yoav Sharoni Aviram Trachtenberg Sultan Tuleukhanov Richard Sensenig Slava Rom Michael Danilenko Zulfiya Orynbayeva |
| author_facet | Saniya Ossikbayeva Marina Khanin Yoav Sharoni Aviram Trachtenberg Sultan Tuleukhanov Richard Sensenig Slava Rom Michael Danilenko Zulfiya Orynbayeva |
| author_sort | Saniya Ossikbayeva |
| collection | DOAJ |
| description | Anticancer activities of plant polyphenols have been demonstrated in various models of neoplasia. However, evidence obtained in numerous in vitro studies indicates that proliferation arrest and/or killing of cancer cells require quite high micromolar concentrations of polyphenols that are difficult to reach in vivo and can also be (geno)toxic to at least some types of normal cells. The ability of certain polyphenols to synergize with one another at low concentrations can be used as a promising strategy to effectively treat human malignancies. We have recently reported that curcumin and carnosic acid applied at non-cytotoxic concentrations synergistically cooperate to induce massive apoptosis in acute myeloid leukemia cells, but not in normal hematopoietic and non-hematopoietic cells, via sustained cytosolic calcium overload. Here, we show that the two polyphenols can also synergistically suppress the growth of DU145 and PC-3 metastatic prostate cancer cell cultures. However, instead of cell killing, the combined treatment induced a marked inhibition of cell proliferation associated with G<sub>0</sub>/G<sub>1</sub> cell cycle arrest. This was preceded by transient elevation of cytosolic calcium levels and prolonged dissipation of the mitochondrial membrane potential, without generating oxidative stress, and was associated with defective oxidative phosphorylation encompassing mitochondrial dysfunction. The above effects were concomitant with a significant downregulation of mRNA and protein expression of the oncogenic kinase SGK1, the mitochondria-hosted mTOR component. In addition, a moderate decrease in SGK1 phosphorylation at Ser422 was observed in polyphenol-treated cells. The mTOR inhibitor rapamycin produced a similar reduction in SGK1 mRNA and protein levels as well as phosphorylation. Collectively, our findings suggest that the combination of curcumin and carnosic acid at potentially bioavailable concentrations may effectively target different types of cancer cells by distinct modes of action. This and similar combinations merit further exploration as an anticancer modality. |
| first_indexed | 2024-03-10T06:45:03Z |
| format | Article |
| id | doaj.art-197e327c10d44571ab5143bd97081474 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T06:45:03Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-197e327c10d44571ab5143bd970814742023-11-22T17:16:23ZengMDPI AGAntioxidants2076-39212021-10-011010159110.3390/antiox10101591Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer CellsSaniya Ossikbayeva0Marina Khanin1Yoav Sharoni2Aviram Trachtenberg3Sultan Tuleukhanov4Richard Sensenig5Slava Rom6Michael Danilenko7Zulfiya Orynbayeva8Department of Surgery, Drexel University College of Medicine, Philadelphia, PA 19102, USADepartment of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be’er Sheva 8410501, IsraelDepartment of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be’er Sheva 8410501, IsraelDepartment of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be’er Sheva 8410501, IsraelDepartment of Biophysics and Biomedicine, Al-Farabi Kazakh National University, Almaty 050040, KazakhstanDepartment of Surgery, Cooper University Hospital, Camden, NJ 08103, USADepartment of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USADepartment of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be’er Sheva 8410501, IsraelDepartment of Surgery, Drexel University College of Medicine, Philadelphia, PA 19102, USAAnticancer activities of plant polyphenols have been demonstrated in various models of neoplasia. However, evidence obtained in numerous in vitro studies indicates that proliferation arrest and/or killing of cancer cells require quite high micromolar concentrations of polyphenols that are difficult to reach in vivo and can also be (geno)toxic to at least some types of normal cells. The ability of certain polyphenols to synergize with one another at low concentrations can be used as a promising strategy to effectively treat human malignancies. We have recently reported that curcumin and carnosic acid applied at non-cytotoxic concentrations synergistically cooperate to induce massive apoptosis in acute myeloid leukemia cells, but not in normal hematopoietic and non-hematopoietic cells, via sustained cytosolic calcium overload. Here, we show that the two polyphenols can also synergistically suppress the growth of DU145 and PC-3 metastatic prostate cancer cell cultures. However, instead of cell killing, the combined treatment induced a marked inhibition of cell proliferation associated with G<sub>0</sub>/G<sub>1</sub> cell cycle arrest. This was preceded by transient elevation of cytosolic calcium levels and prolonged dissipation of the mitochondrial membrane potential, without generating oxidative stress, and was associated with defective oxidative phosphorylation encompassing mitochondrial dysfunction. The above effects were concomitant with a significant downregulation of mRNA and protein expression of the oncogenic kinase SGK1, the mitochondria-hosted mTOR component. In addition, a moderate decrease in SGK1 phosphorylation at Ser422 was observed in polyphenol-treated cells. The mTOR inhibitor rapamycin produced a similar reduction in SGK1 mRNA and protein levels as well as phosphorylation. Collectively, our findings suggest that the combination of curcumin and carnosic acid at potentially bioavailable concentrations may effectively target different types of cancer cells by distinct modes of action. This and similar combinations merit further exploration as an anticancer modality.https://www.mdpi.com/2076-3921/10/10/1591prostate cancercurcumincarnosic acidcell cycleOxPhosSGK1 |
| spellingShingle | Saniya Ossikbayeva Marina Khanin Yoav Sharoni Aviram Trachtenberg Sultan Tuleukhanov Richard Sensenig Slava Rom Michael Danilenko Zulfiya Orynbayeva Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells Antioxidants prostate cancer curcumin carnosic acid cell cycle OxPhos SGK1 |
| title | Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells |
| title_full | Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells |
| title_fullStr | Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells |
| title_full_unstemmed | Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells |
| title_short | Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells |
| title_sort | curcumin and carnosic acid cooperate to inhibit proliferation and alter mitochondrial function of metastatic prostate cancer cells |
| topic | prostate cancer curcumin carnosic acid cell cycle OxPhos SGK1 |
| url | https://www.mdpi.com/2076-3921/10/10/1591 |
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