Transcriptome-wide profiling of human stromal cells in mouse xenografts during preclinical treatment involving chemotherapy and/or the novel senomorphic agent dihydromyricetin

Aging is a major risk factor for the vast majority of geriatric conditions, including various malignancies. Although cancer development can be generally attributed to the accumulation of genetic mutations, biological processes associated with aging also hold the potential to regulate cancer progression. Cellular senescence is a cell state characterized by a permanent cell cycle arrest. Senescent cells tend to accumulate with aging, exhibit pro-inflammatory activities (SASP) and promote cancer development. However, as the effect of cellular senescence on cancer progression is heterogeneous and complicated, detailed mechanisms remain to be unraveled. Fortunately, senescent cells can be eliminated by several strategies, a situation that allows to prevent incidence of chronic disorders and prolong healthspan of mammalians. Strategies involving senolytics, which can selectively remove senescent cells by targeting the SCAP, have recently emerged as a prominent and competent solution to ameliorate diverse age-related pathologies. Achieving the goal using synthetic or natural agents (the latter more preferred in clinical settings) would generate a tremendous impact on the quality of life. Here, we test the potential of dihydromyricetin (DMY), a bioactive compound extracted from Salvia miltiorrhiza, in targeting senescent cells through inhibiting the SASP in a preclinical regimen. This study demonstrates the efficacy of DMY in downregulating the SASP expression and reducing the influence of senescent stromal cells in treatment-damaged tumor microenvironment and provides a strong rationale for its future development in anti-aging pipelines. Overall design: Examination of the in vivo efficacy of DMY in targeting human senescent stromal cells. Experimental mice xenografted with human stromal cells (PCS27) and prostate cancer epithelial cells (PC3) were administered with vehicle, mitoxantrone (MIT) or MIT/DMY as three independent arms in a 8-week preclinical regimen. Upon completion of treatment, mice were sacrificed and tumors were collected for histological analyses. Stromal cells were isolated from tumor tissues by laser capture microdissection (LCM) and subject to RNA preparation, library construction and high throughput sequencing. This trial was performed beyond previous studies reporting DMY effects in treatment of disorders implicating its anti-inflammatory, antioxidant, anticancer and neuroprotective capacities. *************************************************************** The table below lists GEO accessions reused/reanalyzed for this study. ***************************************************************