Abstract. Triple-negative breast carcinoma (TNBC) is one of the most aggressive subtypes of breast cancer and is associated with an unfavorable prognosis. The management of TNBC is currently based on the use of classical cytotoxic drugs, i.e., anthracyclines and/or microtubule-binding agents (TBAs). However, conventional chemotherapy is not always effective in these tumors and a systemic relapse is often observed, potentially due to the development of multi-drug resistance (MDR). Therefore, an improved understanding of MDR mechanisms may improve the therapeutic strategies for TNBC. In the present study, a paclitaxel-resistant (TxR) breast cancer cell subline of HCC1806 TNBC cells was established and characterized. The resistance index of this subline was calculated according to the IC 50 of HCC1806-TxR relative to the parental HCC1806 cells (16.86-fold). TxR-cells also exhibited cross-resistance to vinblastin, doxorubicin and etoposide (~14-, ~4-and ~3-fold, respectively). As assessed with reverse transcription-quantitative polymerase chain reaction, TxR-resistant cells exhibited the upregulated expression of a number of multidrug resistance-associated genes, including MDR-1, MRP-1, -5, -6 and YB-1. The TxR cells also exhibited an increased expression of MDR-related proteins including MDR1 and MRP-1, which led to a substantial increase (5.4-fold) of the paclitaxel efflux from TxR-cells. In addition, the pro-apoptotic protein Fas was downregulated, whereas the anti-apoptotic Bcl-2 was upregulated, in TxR-cells. This may explain why a reduced extent of apoptosis was observed when TxR cells were exposed to TBAs and topoisomerase type II inhibitors, relative to the parental HCC1806 cells. Thus, the HCC1806-TxR cell line may serve as an appropriate model for the analysis of chemoresistance mechanisms in TNBCs, and for the investigation of novel anticancer agents for overcoming MDR-mediated mechanisms in TNBC.
Microtubules are known to be one of the most attractive and validated targets in cancer therapy. However, the clinical use of drugs that affect the dynamic state of microtubules has been hindered by chemoresistance and toxicity issues. Accordingly, the development of novel agents that target microtubules is needed. Here, we report the identification of novel compounds with pirrole and carboxylate structures: ethyl-2-amino-pyrrole-3-carboxylates (EAPCs) that provide potent cytotoxic activities against multiple soft tissue cancer cell lines in vitro. Using the MTS cell proliferation assay, we assessed the activity of EAPCs on various cancer cell lines including leiomyosarcoma SK-LMS-1, rhabdomyosarcoma RD, gastrointestinal stromal tumor GIST-T1, A-673 Ewing's sarcoma, and U-2 OS osteosarcoma. We found that in the majority of cases, two EAPC compounds (EAPC-20 and EAPC-24) considerably inhibited cancer cell proliferation in vitro. The growth-inhibitory effects of EAPC-20 and EAPC-24 were time and dose dependent. The molecular mechanisms of action of these compounds were because of the inhibition of tubulin polymerization and induction of a robust G2/M cell-cycle arrest, leading to considerable accumulation of tumor cells in the M-phase. Finally, EAPCs induced tumor cell death by apoptotic pathways. The above-mentioned effects were also observed in most soft tissue tumor cell lines and the gastrointestinal stromal tumor cell line investigated. Taken together, our data identify potent antitumor activity of EAPCs in vitro, thus providing a novel scaffold with which to develop potent chemotherapeutic agents for cancer therapy.
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