Senolytic Combination Treatment Is More Potent Than Single Drugs in Reducing Inflammatory and Senescence Burden in Cells from Painful Degenerating IVDs
Background: Low back pain is a global health problem directly related to intervertebral disc (IVD) degeneration. Senolytic drugs (RG-7112 and o-Vanillin) target and remove senescent cells from IVDs in vitro, improving tissue homeostasis. One drawback of using a single senolytic agent is the failure...
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| Format: | Article |
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MDPI AG
2023-08-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/8/1257 |
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| author | Matthew Mannarino Oliver Wu-Martinez Kai Sheng Li Li Rodrigo Navarro-Ramirez Peter Jarzem Jean A. Ouellet Hosni Cherif Lisbet Haglund |
| author_facet | Matthew Mannarino Oliver Wu-Martinez Kai Sheng Li Li Rodrigo Navarro-Ramirez Peter Jarzem Jean A. Ouellet Hosni Cherif Lisbet Haglund |
| author_sort | Matthew Mannarino |
| collection | DOAJ |
| description | Background: Low back pain is a global health problem directly related to intervertebral disc (IVD) degeneration. Senolytic drugs (RG-7112 and o-Vanillin) target and remove senescent cells from IVDs in vitro, improving tissue homeostasis. One drawback of using a single senolytic agent is the failure to target multiple senescent antiapoptotic pathways. This study aimed to determine if combining the two senolytic drugs, o-Vanillin and RG-7112, could more efficiently remove senescent cells and reduce the release of inflammatory factors and pain mediators in cells from degenerating human IVDs than either drug alone. Methods: Preliminary data evaluating multiple concentrations of o-Vanillin and RG-7112 led to the selection of four treatment groups. Monolayer and pellet cultures of cells from painful degenerate IVDs were exposed to TLR-2/6 agonist. They were then treated with the senolytics o-Vanillin and RG7112 alone or combined. p16<i><sup>ink4a</sup></i>, Ki-67, caspase-3, inflammatory mediators, and neuronal sprouting were assessed. Results: Compared to the single treatments, the combination of o-Vanillin and RG-7112 significantly reduced the amount of senescent IVD cells, proinflammatory cytokines, and neurotrophic factors. Moreover, both single and combination treatments significantly reduced neuronal sprouting in rat adrenal pheochromocytoma (PC-12 cells). Conclusions: Combining o-Vanillin and RG-7112 greatly enhanced the effect of either senolytic alone. Together, these results support the potential of senolytics as a promising treatment for IVD-related low back pain. |
| first_indexed | 2024-03-11T00:05:52Z |
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| id | doaj.art-e21c59e403a94bd093ec2f44b3e728dc |
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| language | English |
| last_indexed | 2024-03-11T00:05:52Z |
| publishDate | 2023-08-01 |
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| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-e21c59e403a94bd093ec2f44b3e728dc2023-11-19T00:24:27ZengMDPI AGBiomolecules2218-273X2023-08-01138125710.3390/biom13081257Senolytic Combination Treatment Is More Potent Than Single Drugs in Reducing Inflammatory and Senescence Burden in Cells from Painful Degenerating IVDsMatthew Mannarino0Oliver Wu-Martinez1Kai Sheng2Li Li3Rodrigo Navarro-Ramirez4Peter Jarzem5Jean A. Ouellet6Hosni Cherif7Lisbet Haglund8Department of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, CanadaDepartment of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, CanadaDepartment of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, CanadaDepartment of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, CanadaDepartment of Surgery, McGill Scoliosis and Spine Group, McGill University, Montreal, QC H3G 1A4, CanadaDepartment of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, CanadaDepartment of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, CanadaDepartment of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, CanadaDepartment of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, CanadaBackground: Low back pain is a global health problem directly related to intervertebral disc (IVD) degeneration. Senolytic drugs (RG-7112 and o-Vanillin) target and remove senescent cells from IVDs in vitro, improving tissue homeostasis. One drawback of using a single senolytic agent is the failure to target multiple senescent antiapoptotic pathways. This study aimed to determine if combining the two senolytic drugs, o-Vanillin and RG-7112, could more efficiently remove senescent cells and reduce the release of inflammatory factors and pain mediators in cells from degenerating human IVDs than either drug alone. Methods: Preliminary data evaluating multiple concentrations of o-Vanillin and RG-7112 led to the selection of four treatment groups. Monolayer and pellet cultures of cells from painful degenerate IVDs were exposed to TLR-2/6 agonist. They were then treated with the senolytics o-Vanillin and RG7112 alone or combined. p16<i><sup>ink4a</sup></i>, Ki-67, caspase-3, inflammatory mediators, and neuronal sprouting were assessed. Results: Compared to the single treatments, the combination of o-Vanillin and RG-7112 significantly reduced the amount of senescent IVD cells, proinflammatory cytokines, and neurotrophic factors. Moreover, both single and combination treatments significantly reduced neuronal sprouting in rat adrenal pheochromocytoma (PC-12 cells). Conclusions: Combining o-Vanillin and RG-7112 greatly enhanced the effect of either senolytic alone. Together, these results support the potential of senolytics as a promising treatment for IVD-related low back pain.https://www.mdpi.com/2218-273X/13/8/1257low back painintervertebral disc degenerationcellular senescencesenotherapeuticssenolyticscombination therapy |
| spellingShingle | Matthew Mannarino Oliver Wu-Martinez Kai Sheng Li Li Rodrigo Navarro-Ramirez Peter Jarzem Jean A. Ouellet Hosni Cherif Lisbet Haglund Senolytic Combination Treatment Is More Potent Than Single Drugs in Reducing Inflammatory and Senescence Burden in Cells from Painful Degenerating IVDs Biomolecules low back pain intervertebral disc degeneration cellular senescence senotherapeutics senolytics combination therapy |
| title | Senolytic Combination Treatment Is More Potent Than Single Drugs in Reducing Inflammatory and Senescence Burden in Cells from Painful Degenerating IVDs |
| title_full | Senolytic Combination Treatment Is More Potent Than Single Drugs in Reducing Inflammatory and Senescence Burden in Cells from Painful Degenerating IVDs |
| title_fullStr | Senolytic Combination Treatment Is More Potent Than Single Drugs in Reducing Inflammatory and Senescence Burden in Cells from Painful Degenerating IVDs |
| title_full_unstemmed | Senolytic Combination Treatment Is More Potent Than Single Drugs in Reducing Inflammatory and Senescence Burden in Cells from Painful Degenerating IVDs |
| title_short | Senolytic Combination Treatment Is More Potent Than Single Drugs in Reducing Inflammatory and Senescence Burden in Cells from Painful Degenerating IVDs |
| title_sort | senolytic combination treatment is more potent than single drugs in reducing inflammatory and senescence burden in cells from painful degenerating ivds |
| topic | low back pain intervertebral disc degeneration cellular senescence senotherapeutics senolytics combination therapy |
| url | https://www.mdpi.com/2218-273X/13/8/1257 |
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