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Triple-Negative Breast Cancer (TNBC) has a poor prognosis due to lack of targeted therapy. Doxorubicin (DOX) has failed for multiple reasons, including development of multi-drug resistance, induction of inflammation (IL-6 secretion) and long-term toxicities. DOX is also known to have off target proteasomal activation, justifying the concept of combining it with a proteasomal inhibitor. Our study investigated the therapeutic potential of an irreversible proteasome inhibitor carfilzomib (CARF) alone or in combination with DOX in two TNBC cell lines (MDA-MB-231 and MDA-MB-468). CARF was as effective in inhibiting mitosis in vitro for both cell lines in comparison to DOX alone. CARF performed similar to DOX in inhibiting apoptosis but had better results in reducing proliferation. Further studies in MDA-MB-231 cells demonstrated that CARF also inhibited pro-inflammatory IL-6 secretion and NF κB transcriptional activity while DOX stimulated both IL-6 and NF kappa-B activity. The reduction of IL-6 while using CARF highlights its therapeutic potential and ability to enhance current clinical drug regimens. Furthermore, exogenous administration of IL-6 potentiated NF Kappa B transcriptional activity, pSTAT3 (Tyr705) and JAK inflammatory signaling as well as cell proliferation in CARF- or DOX-treated MDA-MB-231 cells. In vivo, CARF treatment resulted in reduced serum IL-6 compared to treatment with DOX in female SCID-NOD mice with MDA-MB-231 cell tumor. A combinational approach using DOX and CARF presents a clinical potential for better efficacy, reduced proliferation, apoptosis, anti-angiogenesis, and less cardiac dysfunction when compared to current treatments using standalone DOX.

Triple negative breast cancer exhibit increased IL-6 expression compared with matched healthy breast tissue and a strong link between inflammation and cancer progression and metastasis has been reported. We investigated whether doxorubicin-hyaluronan-super-paramagnetic iron oxide nanoparticles (DOX-HA-SPION) would show greater therapeutic efficacy in human triple negative breast cancer cells (TNBC) MDA-MB-231, as was recently shown in drug-sensitive and multi-drug-resistant ovarian cancer cells. Therefore, we measured cellular DOX uptake via confocal microscopy; observed morphologic changes: mitochondrial and nuclear changes with electron microscopy, and quantitated apoptosis using FACS analysis after Annexin V and PI staining in MDA-MB-231 cells treated with either DOX alone or DOX-HA-SPION. We also measured both proinflammatory and anti-inflammatory cytokines; IL-6, IL-10 respectively and also measured nitrate levels in the conditioned medium by ELISA. Inaddition, NF-κB activity was measured by luciferase assay. Confocal microscopy demonstrated greater cytoplasmic uptake of DOX-HA-SPION than free DOX. We also demonstrated reduction of Vimentin with DOX-HA-SPION which is significantly less than both control and DOX. DOX-HA-SPION enhanced apoptosis and significantly down regulated both pro-inflammatory mediators IL-6 and NF-κB in comparison to DOX alone. The secretion levels of anti-inflammatory mediators IL-10 and nitrate was not decreased in the DOX or DOX-HA-SPION treatment groups. Our data suggest that DOX-HA-SPION nanomedicine-based drug delivery could have promising potential in treating metastasized and chemoresistant breast cancer by enhancing the drug efficacy and minimizing off-target effects.

Worldwide, breast cancer remains as one of the most common cancer diagnosis and cause of cancer related death among women. Fortunately, nanomedicine has brought forth new potential and hope in breast cancer research. The extremely small size of nanoparticles makes it advantageous and potentially superior to use in tumor detection and imaging. One of the more extensively studied particles is quantum dots, semiconductor crystals which are capable of enhanced labeling and imaging of cancer cells. In addition, due to serious toxicity of chemotherapeutic agents, nano-formulations of breast cancer chemotherapy are under investigation and development. This may provide easier administering route and reduced frequency of drugs. With the use of nanoparticles, drug delivery can be carried out in a minimally invasive fashion and treatment regimens can be made much more targeted and specific for each patient. In this review article, we provide an overview on the role nanomedicine has played in breast cancer and mention some of the latest diagnostic and treatment modalities researched to date.