Transcriptomic profiling of human stromal cells in mouse xenografts upon treatment with chemotherapeutic drug and/or the senolytic agent procyanidin C1

Physical function declines in advanced age, portending disability, increased health expenditures, and clinical mortality. Cellular senescence leads to tissue dysfunction and contributes to the consequences of aging, but whether age-related pathologies including cancer can be alleviated by targeting senescent cells remains largely unclear. Long term retention of senescent cells in vivo, a process mainly attributed to high expression of BCL2 family proteins, causes chronical tissue damages mainly through the senescence-associated secretory phenotype (SASP). Indeed, senescent cells can be removed by several strategies, thus preventing appearance of chronic symptoms and prolonging healthspan. Strategies involving senolytics, which eliminate senescent cells by pharmacological actions, are recently emerging as a novel and prominent solution to ameliorate diverse age-related pathologies. Achieving the goal using synthetic or natural agents would generate a tremendous impact on the quality of life. We test the potential of procyanidin C1 (PCC1), a B type procyanidin flavonoid derived from plant sources including grape, apple and cocoa, in targeting senescent cells through inducing apoptosis and suppressing the pro-inflammatory phenotype. This study demonstrates the efficacy of PCC1 in restraining the SASP expression and minimizing the influence of senescent stromal cells in tumor microenvironment and provides a strong rationale for its future development in anti-aging industrial pipelines. Overall design: Examination of in vitro efficacy of PCC1 in treating human senescent stromal cells. Experimental mice xenografted with human stromal cells (PCS27) and cancer epithelial cells (PC3) were treated with vehicle, mitoxantrone (MIT) or MIT/PCC1 as three independent corhorts in a 8-week preclinical regimen. Upon completion of treatment, mice were sacrificed and tumors were collected for further process. 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 their effects in treatment of disorders including but not limited to osteoporosis, osteoarthritis, atherosclerosis, cancer and neurodegenerative diseases including Alzheimer's and Parkinson's.