RESUMO
Patients with triple-negative breast cancer (TNBC) often have a poor prognosis largely due to lack of effective targeted therapy. Using a library of seleno-purines coupled to a high-throughput biochemical enzymatic assays we identified a potent pharmacological enhancer of autophagy (referred herein as SLLN-15) that selectively activated cytostatic macroautophagy/autophagy in TNBC preclinical models. SLLN-15 induced a dose-dependent anti-proliferative activity in the TNBC cell lines MDA-MB-231 and BT-20 via induction of autophagy and autophagic flux. This induction was associated with a selective inhibition of AKT-MTOR signaling. Conversely, rapamycin, a known autophagy inducer and MTOR inhibitor, was unable to duplicate SLLN-15's effect on TNBC cells. Inhibition of autophagy by siRNA-mediated targeting of the autophagy regulators, BECN1, ATG5 and ATG7 or using 3-methyladenine (3-MA), significantly protected against SLLN-15-induced inhibition of cell viability, further supporting that SLLN-15-induced inhibition of cancer cell proliferation was autophagy-dependent. SLLN-15-induced autophagy in TNBC cells was also associated with decreased AURKA expression, decreased AKT phosphorylation and subsequent blockage of the AKT-MTOR pathway. In vivo, oral SLLN-15 revealed a potent anticancer and anti-metastatic activity in mice bearing TNBC. Altogether, this study describes a novel regulator of mammalian autophagy, with potential utility as an experimental therapeutic for TNBCs. Abbreviations: 3-MA: 3-methyladenine; ATG5: autophagy related 5; ATG7: autophagy related 7; AURKA: aurora kinase A; AURKB: aurora kinase B; BECN1: beclin 1; CQ: chloroquine; DMSO: dimethyl sulfoxide; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; ERBB2: erb-b2 receptor tyrosine kinase 2; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PARP1: poly(ADP-ribose) polymerase 1; PI: propidium iodide; SQSTM1/p62: sequestosome 1; TNBC: triple-negative breast cancer.
Assuntos
Autofagia , Citostáticos/farmacologia , Progressão da Doença , Purinas/farmacologia , Selênio/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Aurora Quinase A/metabolismo , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos SCID , Metástase Neoplásica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Purinas/química , Selênio/química , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Neoplasias de Mama Triplo Negativas/ultraestruturaRESUMO
BACKGROUND: Indoor tanning may increase the risk of melanoma and other health problems. Frequent users of indoor tanning facilities may be at particularly high risk. OBJECTIVE: In study 1 our purpose was to assess the prevalence and nature of indoor tanning advertisements; in study 2 we aimed to assess tanning facility compliance to recommended exposure schedules. METHODS: In study 1, tanning facility advertisements over a 4-month period from 24 San Diego County newspapers were monitored. In study 2, we assessed compliance with recommended exposure schedules via a telephone interview of 60 San Diego County tanning facilities. RESULTS: Approximately 75% of the indoor tanning advertisements promoted unlimited tanning. Only 5% of facilities were in compliance with recommended tanning schedules, and 100% offered "unlimited" tanning packages. CONCLUSIONS: These findings suggest that the indoor tanning industry, through pricing incentives that allow frequent sessions, may be promoting overexposure to UVR. Stronger legislation is needed to address this issue.