Killing senescent cells and treating senescence-associated conditions using a src inhibitor and a flavonoid

Abstract

Provided herein are methods and uses for treatment or prophylaxis of a senescent cell associated disease or disorder by administering a senolytic combination comprising dasatinib and quercetin or an analog thereof to a subject in need thereof. In certain embodiments, the senescent cell associated disease or disorder is a cardiovascular disease or disorder, inflanunatory disease or disorder, a pulmonary disease or disorder, a neurological disease or disorder, or a metabolic disease or disorder.

1 . A method for treating a senescence associated disease or disorder in a subject comprising administering to the subject a senolytic combination, which senolytic combination comprises (a) a first agent that alters either one or both of a cell survival signaling pathway and an inflammatory pathway; and (b) a second agent that alters either one or both of a cell survival signaling pathway and an inflammatory pathway; wherein the senescence associated disease or disorder is not a cancer, and wherein the senolytic combination is administered during a treatment course of 1-7 days every 0.5-12 months; provided that if the senescence associated disease or disorder is a senescence associated metabolic disorder, the senolytic combination is administered during a treatment course of 1-7 days every 4-12 months. 
     
     
         2 . The method of  claim 1 , wherein the senolytic combination is administered once every 0.5-12 months; provided that if the senescence associated disease or disorder is a senescence associated metabolic disorder, the senolytic combination is administered once every 4-12 months. 
     
     
         3 . The method of  claim 1 , wherein the senescent cell-associated disease or disorder is a cardiovascular disease or disorder, inflammatory disease or disorder, a pulmonary disease or disorder, a neurological disease or disorder. 
     
     
         4 . The method of  claim 3 , wherein the cardiovascular disease or disorder is atherosclerosis. 
     
     
         5 . The method of  claim 3 , wherein the inflammatory disease or disorder is osteoarthritis. 
     
     
         6 . The method of  claim 3 , wherein the pulmonary disease or disorder is idiopathic pulmonary fibrosis or chronic obstructive pulmonary disease. 
     
     
         7 . The method of  claim 3  wherein the neurological disease or disorder is selected from mild cognitive impairment; motor neuron dysfunction; Alzheimer's disease; Parkinson's disease; and macular degeneration. 
     
     
         8 . The method of  claim 1 , wherein the senescence associated metabolic disease or disorder is selected from diabetes, metabolic syndrome, and obesity. 
     
     
         9 . The method of  claim 1 , wherein the senescence-associated disease or disorder is a dermatological disease or disorder is selected from eczema, psoriasis, hyperpigmentation, nevi, rashes, atopic dermatitis, urticaria, diseases and disorders related to photosensitivity or photoaging, rhytides; pruritis; dysesthesia; eczematous eruptions; eosinophilic dermatosis; reactive neutrophilic dermatosis; pemphigus; pemphigoid; immunobullous dermatosis; fibrohistocytic proliferations of skin; cutaneous lymphomas; and cutaneous lupus. 
     
     
         10 . A method for treating a senescence-associated metabolic disease or disorder in a subject comprising administering to the subject a senolytic combination, which senolytic combination comprises (a) a first agent that alters either one or both of a cell survival signaling pathway and an inflammatory pathway; and (b) a second agent that alters either one or both of a cell survival signaling pathway and an inflammatory pathway, wherein the senolytic combination is administered during a treatment course of 1-7 days every 4-12 months, and wherein the metabolic disease or disorder is selected from diabetes, metabolic syndrome, and obesity. 
     
     
         11 . The method of  claim 10 , wherein the senolytic combination is administered once every 4-12 months. 
     
     
         12 . The method of  claim 1 , wherein the senescent cell is selected from a senescent fibroblast, a senescent pre-adipocyte, a senescent epithelial cell, a senescent chondrocyte, a senescent neuron, and a senescent endothelial cell. 
     
     
         13 . The method of  claim 10 , wherein the senescent cell is a senescent pre-adipocyte. 
     
     
         14 . The method of  claim 1 , wherein the first agent is a src inhibitor and wherein the second agent is a flavonoid. 
     
     
         15 . The method of  claim 14 , wherein the first agent is dasatinib and the second agent is a compound having a structure of the following formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, wherein 
         R 1  is —OH or H; 
         R 2  is —OH or H; 
         R 3  is —OH, H, R 6 , or —OCH 2 PO(OH) 2 ; 
         R 4  is —OH, —OPO(OH)(O − ), —OCH 3 , —OCH 2 PO(OH) 2 , R 6 , H, or —OSO3 − ; and 
         R 5  is —OH, H, R 6 , or —OCH 3 , 
         wherein R 6  is 
       
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 15  wherein R 3  is —OH, R 6 , or —OCH 2 PO(OH) 2 . 
     
     
         17 . The method of  claim 15  wherein R 3  is —OH. 
     
     
         18 . The method of  claim 15  wherein R 4  is —OH, —OPO(OH)(O − ), —OCH 3 , —OCH 2 PO(OH) 2 , R 6 , or —OSO 3   − . 
     
     
         19 . The method of  claim 15  wherein R 4  is —OH, —OPO(OH)(O − ), —OCH 2 PO(OH) 2 , R 6 , or —OSO 3   − . 
     
     
         20 . The method of  claim 15  wherein R 4  is —OH, or —OSO 3   − . 
     
     
         21 . The method of  claim 15  wherein R 5  is —OH or R 6 . 
     
     
         22 . The method of  claim 15  wherein the compound of Formula (I) is selected from: