Differential Mechanisms of Cell Death Induced by HDAC Inhibitor SAHA and MDM2 Inhibitor RG7388 in MCF-7 Cells
Gene expression is often altered by epigenetic modifications that can significantly influence the growth ability and progression of cancers. SAHA (Suberoylanilide hydroxamic acid, also known as Vorinostat), a well-known Histone deacetylase (HDAC) inhibitor, can stop cancer growth and metastatic proc...
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MDPI AG
2018-12-01
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| Series: | Cells |
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| Online Access: | http://www.mdpi.com/2073-4409/8/1/8 |
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| author | Umamaheswari Natarajan Thiagarajan Venkatesan Vijayaraghavan Radhakrishnan Shila Samuel Appu Rathinavelu |
| author_facet | Umamaheswari Natarajan Thiagarajan Venkatesan Vijayaraghavan Radhakrishnan Shila Samuel Appu Rathinavelu |
| author_sort | Umamaheswari Natarajan |
| collection | DOAJ |
| description | Gene expression is often altered by epigenetic modifications that can significantly influence the growth ability and progression of cancers. SAHA (Suberoylanilide hydroxamic acid, also known as Vorinostat), a well-known Histone deacetylase (HDAC) inhibitor, can stop cancer growth and metastatic processes through epigenetic alterations. On the other hand, Letrozole is an aromatase inhibitor that can elicit strong anti-cancer effects on breast cancer through direct and indirect mechanisms. A newly developed inhibitor, RG7388 specific for an oncogene-derived protein called MDM2, is in clinical trials for the treatment of various cancers. In this paper, we performed assays to measure the effects of cell cycle arrest resulting from individual drug treatments or combination treatments with SAHA + letrozole and SAHA + RG7388, using the MCF-7 breast cancer cells. When SAHA was used individually, or in combination treatments with RG7388, a significant increase in the cytotoxic effect was obtained. Induction of cell cycle arrest by SAHA in cancer cells was evidenced by elevated p21 protein levels. In addition, SAHA treatment in MCF-7 cells showed significant up-regulation in phospho-RIP3 and MLKL levels. Our results confirmed that cell death caused by SAHA treatment was primarily through the induction of necroptosis. On the other hand, the RG7388 treatment was able to induce apoptosis by elevating BAX levels. It appears that, during combination treatments, with SAHA and RG7388, two parallel pathways might be induced simultaneously, that could lead to increased cancer cell death. SAHA appears to induce cell necroptosis in a p21-dependent manner, and RG7388 seems to induce apoptosis in a p21-independent manner, outlining differential mechanisms of cell death induction. However, further studies are needed to fully understand the intracellular mechanisms that are triggered by these two anti-cancer agents. |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T08:15:05Z |
| publishDate | 2018-12-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-9a80cd08c016419db8252f56d91aa7d62023-09-02T18:57:43ZengMDPI AGCells2073-44092018-12-0181810.3390/cells8010008cells8010008Differential Mechanisms of Cell Death Induced by HDAC Inhibitor SAHA and MDM2 Inhibitor RG7388 in MCF-7 CellsUmamaheswari Natarajan0Thiagarajan Venkatesan1Vijayaraghavan Radhakrishnan2Shila Samuel3Appu Rathinavelu4VRR Institute of Biomedical Sciences, Kattupakkam, Chennai 600056, IndiaRumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, Ft. Lauderdale, FL 33314, USAVRR Institute of Biomedical Sciences, Kattupakkam, Chennai 600056, IndiaVRR Institute of Biomedical Sciences, Kattupakkam, Chennai 600056, IndiaRumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, Ft. Lauderdale, FL 33314, USAGene expression is often altered by epigenetic modifications that can significantly influence the growth ability and progression of cancers. SAHA (Suberoylanilide hydroxamic acid, also known as Vorinostat), a well-known Histone deacetylase (HDAC) inhibitor, can stop cancer growth and metastatic processes through epigenetic alterations. On the other hand, Letrozole is an aromatase inhibitor that can elicit strong anti-cancer effects on breast cancer through direct and indirect mechanisms. A newly developed inhibitor, RG7388 specific for an oncogene-derived protein called MDM2, is in clinical trials for the treatment of various cancers. In this paper, we performed assays to measure the effects of cell cycle arrest resulting from individual drug treatments or combination treatments with SAHA + letrozole and SAHA + RG7388, using the MCF-7 breast cancer cells. When SAHA was used individually, or in combination treatments with RG7388, a significant increase in the cytotoxic effect was obtained. Induction of cell cycle arrest by SAHA in cancer cells was evidenced by elevated p21 protein levels. In addition, SAHA treatment in MCF-7 cells showed significant up-regulation in phospho-RIP3 and MLKL levels. Our results confirmed that cell death caused by SAHA treatment was primarily through the induction of necroptosis. On the other hand, the RG7388 treatment was able to induce apoptosis by elevating BAX levels. It appears that, during combination treatments, with SAHA and RG7388, two parallel pathways might be induced simultaneously, that could lead to increased cancer cell death. SAHA appears to induce cell necroptosis in a p21-dependent manner, and RG7388 seems to induce apoptosis in a p21-independent manner, outlining differential mechanisms of cell death induction. However, further studies are needed to fully understand the intracellular mechanisms that are triggered by these two anti-cancer agents.http://www.mdpi.com/2073-4409/8/1/8SAHARG7388necroptosisapoptosisp21phospho-RIP3MLKLMCF-7 |
| spellingShingle | Umamaheswari Natarajan Thiagarajan Venkatesan Vijayaraghavan Radhakrishnan Shila Samuel Appu Rathinavelu Differential Mechanisms of Cell Death Induced by HDAC Inhibitor SAHA and MDM2 Inhibitor RG7388 in MCF-7 Cells Cells SAHA RG7388 necroptosis apoptosis p21 phospho-RIP3 MLKL MCF-7 |
| title | Differential Mechanisms of Cell Death Induced by HDAC Inhibitor SAHA and MDM2 Inhibitor RG7388 in MCF-7 Cells |
| title_full | Differential Mechanisms of Cell Death Induced by HDAC Inhibitor SAHA and MDM2 Inhibitor RG7388 in MCF-7 Cells |
| title_fullStr | Differential Mechanisms of Cell Death Induced by HDAC Inhibitor SAHA and MDM2 Inhibitor RG7388 in MCF-7 Cells |
| title_full_unstemmed | Differential Mechanisms of Cell Death Induced by HDAC Inhibitor SAHA and MDM2 Inhibitor RG7388 in MCF-7 Cells |
| title_short | Differential Mechanisms of Cell Death Induced by HDAC Inhibitor SAHA and MDM2 Inhibitor RG7388 in MCF-7 Cells |
| title_sort | differential mechanisms of cell death induced by hdac inhibitor saha and mdm2 inhibitor rg7388 in mcf 7 cells |
| topic | SAHA RG7388 necroptosis apoptosis p21 phospho-RIP3 MLKL MCF-7 |
| url | http://www.mdpi.com/2073-4409/8/1/8 |
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