Autophagy inhibition augments the anticancer effects of epirubicin treatment in anthracycline-sensitive and -resistant triple-negative breast cancer IMI CONFIDENTIAL Clinical Cancer Research, Published OnlineFirst April 10, 2014, IF=8.193 古春博

2 IMI CONFIDENTIAL Introduction  Triple-negative breast cancer (TNBC) was coined in 2005 for cancers lacking detectable expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/NEU/ERBB2).  Patients with TNBC have poorer outcomes due to drug resistance and more aggressive recurrent disease compared with other subtypes.  Autophagy has a cytoprotective function that enables cancer cells to cope with cytotoxic or other stresses induced by treatment. Thus, anticancer therapies commonly lead to the upregulation of autophagy.

FDA-approved chloroquine or hydroxychloroquine in combination with chemo- or radiotherapy for the treatment of different cancers, including breast, colon, brain, prostate, and non–small cell lung cancers, are currently under way. In this study, we show that epirubicin induced autophagic flux in TNBC cell lines.We developed anthracycline-resistant TNBC cell lines and demonstrate that in the absence of treatment, they exhibit relatively high levels of autophagic flux, compared with their parental cell lines. We provide evidence supporting the effective combination of epirubicin with pharmacologic (chloroquine and hydroxychloroquine) or genetic (siRNA) inhibition of autophagy, both in TNBC parental cell lines and their derivative anthracycline-resistant lines, in vitro and in xenograft mouse models.

Figure 1. Epirubicin treatment reduces cell viability and increases autophagic flux in TNBC cells

Figure 2 TNBC cells resistant to epirubicin have higher levels of autophagic flux relative to parent cells.

Figure 3. Combinatio n treatment of autophagy inhibition and epirubicin enhances the loss in cell viability.

Figure 4. Autophagy inhibition reduces viability and augments cell death of TNBC lines resistant to epirubicin.

Figure 5. Assessment of in vivo autophagy- related protein levels in MDA-MB- 231 xenograft tumors.

Figure 6. Combinatorial epirubicin (EPI) and hydroxychloroqui ne (HCQ) treatment reduces growth in MDA- MB-231 and MDA-MB-231- R8 tumor xenograft models.

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