BackgroundConcerns about breast cancer had become the most dangerous cancer to women over the world, more and more anti‐cancer agents are developed to treat this malignancy. Pharmorubicin is a cytotoxic drug, widely used in the treatment of breast cancer, but its role is limited because of chemoresistance produced by cells. This study focused on exploring the influence of autophagy on the resistance of pharmorubicin in breast cancer cells.MethodsThe cell survival of breast cancer cells was detected by MTT. The mRNA expression of heme oxygenase‐1 (HO‐1) was tested by qRT‐PCR. The protein expression of HO‐1, autophagic proteins (LC3‐I,LC3‐II and Beclin‐1), PI3K and Akt was detected by Western blot. Cell autophagy was examined by Cyto‐ID Autophagy Detection Kit.ResultsAfter being treated with pharmorubicin, the expression of HO‐1 and autophagy related proteins was significantly enhanced, but the cell survival ratio in the two cell lines decreased. After autophagy was inhibited, HO‐1 expression in two cells was down‐regulated. When pharmorubicin‐resistant cells were transfected with si‐HO‐1, the cell survival decreased and the protein expression of HO‐1, autophagic proteins (LC3‐II/LC3‐I and Beclin‐1) as well as autophagy were all down‐regulated, while in pharmorubicin‐resistant cells transfected with pcDNA3.1‐HO‐1, the results were reverse. When the PI3K or Akt was inhibited, PI3K, p‐Akt, HO‐1, autophagic proteins and autophagy were decreased remarkably.ConclusionIt was proved that HO‐1 induction mediated chemoresistance of pharmorubicin in breast cancer cells by promoting autophagy via PI3K/Akt pathway.

Anthrax toxin is the major virulence factor produced by Bacillus anthracis. The toxin consists of three protein subunits: protective antigen (PA), lethal factor, and edema factor. Inhibition of PA binding to its receptors, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2) can effectively block anthrax intoxication, which is particularly valuable when the toxin has already been overproduced at the late stage of anthrax infection, thus rendering antibiotics ineffectual. Receptor-like agonists, such as the mammalian cell-expressed von Willebrand factor type A (vWA) domain of CMG2 (sCMG2), have demonstrated potency against the anthrax toxin. However, the soluble vWA domain of TEM8 (sTEM8) was ruled out as an anthrax toxin inhibitor candidate due to its inferior affinity to PA. In the present study, we report that L56A, a PA-binding-affinity-elevated mutant of sTEM8, could inhibit anthrax intoxication as effectively as sCMG2 in Fisher 344 rats. Additionally, pharmacokinetics showed that L56A and sTEM8 exhibit advantages over sCMG2 with better lung-targeting and longer plasma retention time, which may contribute to their enhanced protective ability in vivo. Our results suggest that receptor decoys based on TEM8 are promising anthrax toxin inhibitors and, together with the pharmacokinetic studies in this report, may contribute to the development of novel anthrax drugs.

MINT‐7014735, MINT‐7014747, MINT‐7014761: PA63 (uniprotkb:P13423) and LF (uniprotkb:P15917) bind (MI:0407) by surface plasmon resonance (MI:0107)

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