Blockage of glutamine-dependent anaplerosis affects mTORC1/2 activity and ultimately leads to cellular senescence-like response.

The purpose of study was to explore the role of glutamine-dependent anaplerosis in cell fate determination (proliferation and senescence) and the potential associated mechanism by employing a pharmacological inhibitor of glutamine-dependent anaplerosis, amino-oxyacetate (AOA). Using the WI38 normal human embryonic fibroblast cell line, we found that exposure to AOA induced mTORC1 inactivation-mTORC2 activation (within day 1), cell cycle arrest (day 2-6) and cellular senescence (day 4-6). These AOA effects were blocked by concomitantly providing anaplerotic factors [α-ketoglutarate (αKG), pyruvate or oxaloacetate], and not affected by ROS scavenger N-acetyl-cysteine (NAC). Moreover, AOA-induced cellular senescence in WI38 cells is associated with elevated protein levels of p53, p21CIP1 and p16INK4A and decreased Rb protein level, which was blocked by αKG supplementation. In p16INK4A-deficient U2OS human osteosarcoma cells and p16INK4A-knockdown WI38 cells, AOA exposure also induced similar effects on cell proliferation, and protein level of P-Rb-S807/811 and Rb. Interestingly, no AOA induction of cellular senescence was observed in U2OS cells, yet was still seen in p16INK4A-knockdown WI38 cells accompanied by the presence of p16 antibody-reactive p12. In summary, we disclose that glutamine-dependent anaplerosis is essential to cell growth and closely associated with mTORC1 activation and mTORC2 inactivation, and impedes cellular senescence particularly associated with p16INK4A.

Traditional Chinese medicine is associated with a decreased risk of heart failure in breast cancer patients receiving doxorubicin treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Cardiovascular disease is the main concern of breast cancer survivors who received doxorubicin treatment. Traditional Chinese medicine (TCM) provides as a complementary therapy to patients with breast cancer and is an important component of health care in Taiwan. However, the TCM utilization patterns and it's efficacy in breast cancer patients is unknown. MATERIALS AND METHODS: From a sample of claims data collected over the period of 1997-2010 in Taiwan, we identified 24,457 breast cancer patients who received TCM treatments and 24,457 breast cancer patients who did not receive TCM treatments. All enrollment patients had received doxorubicin chemotherapy. These patients were paired by age; index day; and propensity score for selected comorbidities, Herceptin and tamoxifen. The incidence of cumulative congestive heart failure (CHF) was compared between cohorts. Fine and Gray regression hazard model was used to evaluate the risk of CHF. RESULTS: After adjusting for age, Herceptin, tamoxifen, diabetic drug, cardiovascular drug, statin and comorbidities, the stratified Fine and Gray model revealed that the TCM cohort had an adjusted subdistribution hazard ratio (sHR) of 0.68 (95% confidence interval (CI) = 0.62-0.76, p < 0.0001) for the development of CHF. In addition, the sub-cohort analysis revealed that the Baihuasheshecao cohort compared to the non-TCM cohort had an adjusted sHR of 0.29 (95% CI = 0.15-0.56, p = 0.0002) for the development of CHF. CONCLUSION: Using TCM significantly decreased the incidence of CHF in patients with breast cancer who received conventional chemotherapy with or without radiotherapy.