IMD-0354 Targets Breast Cancer Stem Cells: A Novel Approach for an Adjuvant to Chemotherapy to Prevent Multidrug Resistance in a Murine Model

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.

Cryoablation and Meriva have strong therapeutic effect on triple-negative breast cancer

“…Both TAAs are highly expressed in the lung metastases and tumor of the 4T1 model. 26 As shown in Figure 3A, B, the production of IFNg by spleen cells restimulated with both TAAs Mage-b and Survivin of mice receiving cryoablation and Meriva, was significantly higher compared to all control groups. In addition, depletion of CD8 C T cells in the spleen cultures of mice receiving cryoablation and Meriva resulted in a significant reduction in the number of IFNg-producing spleen cells compared to non-CD8…”

Targeting STING pathways for the treatment of cancer

“…C T-cell responses to TAAs Mage-b and Survivin, both highly expressed by 4T1 tumor cells, 8,9 were observed in the spleens of mice treated with 1 high and multiple low doses of c-di-GMP. Also, this combination resulted in a near elimination of all metastases and a significant decrease in tumor growth.…”

Exosome‑mediated peritoneal dissemination in gastric cancer and its clinical applications (Review)

“…For example, engineered exosomes loaded with doxorubicin can be safely delivered to the tumor microenvironment, demonstrating similar tumor growth inhibition with less adverse effects compared with equipotent free drug (56)(57)(58) (60) demonstrated that exosomes loaded with HGF siRNA could inhibit tumor growth and angiogenesis in gastric cancer. It is hoped that an exosome-based approach for the treatment of gastric cancer with or without peritoneal dissemination will be developed in the near future.…”