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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. p16ink4a, 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.<\/jats:p>","DOI":"10.3390\/biom13081257","type":"journal-article","created":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T10:15:48Z","timestamp":1692267348000},"page":"1257","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Senolytic Combination Treatment Is More Potent Than Single Drugs in Reducing Inflammatory and Senescence Burden in Cells from Painful Degenerating IVDs"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7086-7396","authenticated-orcid":false,"given":"Matthew","family":"Mannarino","sequence":"first","affiliation":[{"name":"Department of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Department of Surgery, McGill Scoliosis and Spine Group, McGill University, Montreal, QC H3G 1A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Wu-Martinez","sequence":"additional","affiliation":[{"name":"Department of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Department of Surgery, McGill Scoliosis and Spine Group, McGill University, Montreal, QC H3G 1A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Department of Surgery, McGill Scoliosis and Spine Group, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Shriner\u2019s Hospital for Children, Montreal, QC H4A 0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6342-0633","authenticated-orcid":false,"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Department of Surgery, McGill Scoliosis and Spine Group, McGill University, Montreal, QC H3G 1A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Navarro-Ramirez","sequence":"additional","affiliation":[{"name":"Department of Surgery, McGill Scoliosis and Spine Group, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Shriner\u2019s Hospital for Children, Montreal, QC H4A 0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Jarzem","sequence":"additional","affiliation":[{"name":"Department of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Department of Surgery, McGill Scoliosis and Spine Group, McGill University, Montreal, QC H3G 1A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean A.","family":"Ouellet","sequence":"additional","affiliation":[{"name":"Department of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Department of Surgery, McGill Scoliosis and Spine Group, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Shriner\u2019s Hospital for Children, Montreal, QC H4A 0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0703-3898","authenticated-orcid":false,"given":"Hosni","family":"Cherif","sequence":"additional","affiliation":[{"name":"Department of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Department of Surgery, McGill Scoliosis and Spine Group, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Shriner\u2019s Hospital for Children, Montreal, QC H4A 0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1288-2149","authenticated-orcid":false,"given":"Lisbet","family":"Haglund","sequence":"additional","affiliation":[{"name":"Department of Surgery, Orthopaedic Research Laboratory, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Department of Surgery, McGill Scoliosis and Spine Group, McGill University, Montreal, QC H3G 1A4, Canada"},{"name":"Shriner\u2019s Hospital for Children, Montreal, QC H4A 0A9, Canada"},{"name":"Montreal General Hospital, 1650 Cedar Avenue, C.10.166, Montreal, QC H3G 1A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,16]]},"reference":[{"key":"ref_1","unstructured":"Global Burden of Disease Study 2013 Collaborators (2015). 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