Abstract
Although early detection of breast cancer improved in recent years, prognosis of patients with late stage breast cancer remains poor, mostly due to development of multidrug resistance (MDR) followed by tumor recurrence. Cancer stem cells (CSCs), with higher drug efflux capability and other stem cell-like properties, are concentrated in a side population (SP) of cells, which were proposed to be responsible for MDR and tumor repopulation that cause patients to succumb to breast cancer. Therefore, targeting of CSCs as an adjuvant to chemotherapy should be able to provide a more effective treatment of this disease. Here, we used IMD-0354, an inhibitor of NF-κB, identified for targeting CSCs, in a combination therapy with doxorubicin encapsulated in targeted nanoparticles. IMD-0354 did target CSCs, evidenced by a decrease in the SP, demonstrated by the inhibition of the following: dye/drug efflux, reduction in ABC transporters as well as in colony formation in soft agar and low attachment plates. Decrease of stem-like gene expression of Oct4, Nanog and Sox2, and apoptosis resistance related to the Survivin gene also was observed after treatment with this compound. In addition, IMD-0354 targeted non-CSCs as indicated by reducing viability and increasing apoptosis. Targeted drug delivery, achieved with a legumain inhibitor, proved to enhance drug delivery under hypoxia, a hallmark of the tumor microenvironment, but not under normoxia. Together, this allowed a safe, non-toxic delivery of both anticancer agents to the tumor microenvironment of mice bearing syngeneic metastatic breast cancer. Targeting both bulk tumor cells with a chemotherapeutic agent and CSCs with IMD-0354 should be able to reduce MDR. This could eventually result in decreasing tumor recurrences and/or improve the outcome of metastatic disease.
Highlights
Breast cancer is the second most commonly diagnosed malignancy among American women, and is second in cancer related deaths [1]
The improved efficiency of targeted nanoparticles (tNPs)-Dox reducing firefly luciferase expressing 4T1 (FL4T1) viability was observed when its cytotoxic effect was compared between normoxia and hypoxia: viability was reduced from 60–100% to 40-15% (Figure 6G). These results indicate that tNP could facilitate an effective, safe delivery vehicle for Dox or combination therapy treatment
Many breast cancer-related deaths are due to multiple drug resistance (MDR) and cancer recurrence
Summary
Breast cancer is the second most commonly diagnosed malignancy among American women, and is second in cancer related deaths [1]. Death rates from breast cancer decreased modestly over the last few years, more efficient therapies are urgently needed, especially in the case of aggressively invading breast cancer. Treatment of breast cancer with radio- and/or chemotherapy frequently leads to multiple drug resistance (MDR) and tumor recurrence. Doxorubicin (Dox) is a chemotherapeutic drug commonly used to treat breast cancer. Its side effects, cardiac toxicity, make it a poor option for cancer treatment [2]. Encapsulation of Dox into liposomal nanoparticles, considerably reduced heart toxicity. Nonspecificity of these lipid nanoparticles does not reduce toxicity in other organs [3]. Major improvements are required for the safe and effective chemotherapy of breast and other solid tumors
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