Abstract
Doxorubicin (Dox), one of the most effective chemotherapy drug for cancer treatment, is limited by its severe side effects and chemoresistance. Dox induces DNA damage and leads to significant proteomic changes in the cancer cells, which makes the ubiquitin-proteasome system a potential target to enhance the efficacy of Dox therapy. The unsuccessful clinical trials of proteasome inhibitor PS-341 (bortezomib) in solid tumors led to the invention of MLN9708 (ixazomib), an orally bioavailable next-generation proteasome inhibitor with improved pharmacokinetic and pharmacodynamic features. In this preclinical study, we used eight human breast cancer cell lines, which represent the major molecular subtypes of breast cancer, to validate the cytotoxic effects of MLN9708, alone and in combination with Dox. We found that MLN9708 had cytotoxic effects, induced autophagy and MKP-1 expression, and enhanced Dox-induced apoptosis in these cell lines. MLN9708 also enhanced Dox-induced JNK and p38 phosphorylation and inhibited Dox-induced IκBα degradation. Our in vitro results suggest that MLN9708 has antitumor effects in breast cancer and can sensitize breast cancer cells to Dox treatment. This promising combination may be an effective and feasible therapeutic option for treating breast cancer and warrants clinical validation.
Highlights
IDC, pap become a promising anticancer strategy[14]
By using a panel of breast cancer cell lines including T47D, MCF7, MDA-MB-361, SK-BR-3, HCC1954, MDA-MB-468, MDA-MB-231, and BT-549 (Table 1)[26,27,28], we examined the cytotoxic effects of MLN9708 and whether MLN9708 could sensitize breast cancer cells to Dox-induced apoptosis
Since the median inhibitory concentration (IC50) values of MLN9708 were around the doses of 0.1 μM and 0.3 μM within all cell lines, we only show data from samples treated with these two doses
Summary
IDC, pap become a promising anticancer strategy[14]. Several studies have verified that inhibiting the proteasome can suppress the degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (IκB), which inhibits NF-κB nuclear translocation and activation[15,16]. The results from clinical trials indicate that PS-341 and PS-341–containing therapies are not effective for the treatment of solid tumors including breast cancer due to the inability of PS-341 to penetrate into tumors and achieve therapeutically relevant concentrations in tumor[19,20,21,22]. MLN9708 (ixazomib), the next-generation proteasome inhibitor, has been shown to have potent anticancer activity in both hematologic and solid tumor xenograft models with better pharmacokinetic and pharmacodynamic features than PS-34123. Accumulating evidence indicates that MLN9708 could be a possible therapy for the treatment of solid tumors including breast cancer[24,25]. By using a panel of breast cancer cell lines including T47D, MCF7, MDA-MB-361, SK-BR-3, HCC1954, MDA-MB-468, MDA-MB-231, and BT-549 (representing ER/PR+/−, HER2+, or triple negative, respectively) (Table 1)[26,27,28], we examined the cytotoxic effects of MLN9708 and whether MLN9708 could sensitize breast cancer cells to Dox-induced apoptosis
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