ACT001 can prevent and reverse tamoxifen resistance in human breast cancer cell lines by inhibiting NF-κB activation.

Endocrine therapy is one of the main treatments for estrogen receptor-positive breast cancers. Tamoxifen is the most commonly used drug for endocrine therapy. However, primary or acquired tamoxifen resistance occurs in a large proportion of breast cancer patients, leading to therapeutic failure. We found that the combination of tamoxifen and ACT001, a nuclear factor-κB (NF-κB) signaling pathway inhibitor, effectively inhibited the proliferation of both tamoxifen-sensitive and tamoxifen-resistant cells. The tamoxifen-resistant cell line MCF7R/LCC9 showed active NF-κB signaling and high apoptosis-related gene transcription, especially for antiapoptotic genes, which could be diminished by treatment with ACT001. These results demonstrate that ACT001 can prevent and reverse tamoxifen resistance by inhibiting NF-κB activation.

Sulforaphane Analogues with Heterocyclic Moieties: Syntheses and Inhibitory Activities against Cancer Cell Lines.

Recent studies have shown that sulforaphane (SFN) selectively inhibits the growth of ALDH⁺ breast cancer stem-like cells.Herein, a series of SFN analogues were synthesized and evaluated against breast cancer cell lines MCF-7 and SUM-159, and the leukemia stem cell-like cell line KG-1a. These SFN analogues were characterized by the replacement of the methyl group with heterocyclic moieties, and the replacement of the sulfoxide group with sulfide or sulfone. A growth inhibitory assay indicated that the tetrazole analogs 3d, 8d and 9d were significantly more potent than SFN against the three cancer cell lines. Compound 14c, the water soluble derivative of tetrazole sulfide 3d, demonstrated higher potency against KG-1a cell line than 3d. SFN, 3d and 14c significantly induced the activation of caspase-3, and reduced the ALDH⁺ subpopulation in the SUM159 cell line, while the marketed drug doxrubicin(DOX) increased the ALDH⁺ subpopulation.

CHL1 is involved in human breast tumorigenesis and progression.

Neural cell adhesion molecules (CAM) play important roles in the development and regeneration of the nervous system. The L1 family of CAMs is comprised of L1, Close Homolog of L1 (CHL1, L1CAM2), NrCAM, and Neurofascin, which are structurally related trans-membrane proteins in vertebrates. Although the L1CAM has been demonstrated play important role in carcinogenesis and progression, the function of CHL1 in human breast cancer is limited. Here, we found that CHL1 is down-regulated in human breast cancer and related to lower grade. Furthermore, overexpression of CHL1 suppresses proliferation and invasion in MDA-MB-231 cells and knockdown of CHL1 expression results in increased proliferation and invasion in MCF7 cells in vitro. Finally, CHL1 deficiency promotes tumor formation in vivo. Our results may provide a strategy for blocking breast carcinogenesis and progression.

[Docetaxel and capecitabine combination chemotherapy for patients with anthracycline-resistant metastatic breast cancer].

OBJECTIVE: To evaluate the efficacy and safety of docetaxel and capecitabine combination chemotherapy (DC regimen) for patients with anthracycline-resistant metastatic breast cancer. METHODS: Thirty-two patients with anthracycline-resistant metastatic breast cancer were treated with a docetaxel and capecitabine combination regimen. All patients received oral administration of capecitabine at a dose of 1250 mg/m(2) twice daily, within 30 min after meal on D1 to D14, and intravenous infusion of docetaxel at a dose of 75 mg/m(2) on D1. The regimen was repeated every 3 weeks. RESULTS: A total of 126 cycles of DC regimen were administered in the 32 cases, with a median of 4 cycles. The overall response rate was 46.9%. Among the 32 patients, there were complete response in 1, partial response in 14, stable disease in 11 and progressive disease in 6 cases. The median time to progression (TTP) was 5.6 months. The one-year survival rate was 56.3%. The effective cases in different metastatic organs were: 8 cases in the lung, 6 cases in the liver, 3 cases in the soft tissue and 3 cases in the lymph nodes. The common adverse reactions were myelosuppression, hand-foot syndrome, nausea and vomiting. Neutropenia was observed in 84.4% of the patients. Two patients developed degree IV myelosuppression. CONCLUSION: The combination chemotherapy regimen of docetaxel plus capecitabine is well-tolerated and effective for anthracycline-resistant metastatic breast cancer.

Potential role of pemetrexed in metastatic breast cancer patients pre-treated with anthracycline or taxane.

OBJECTIVES: This article reviews pharmacology, pharmacokinetic properties, clinical efficacy, and safety in metastatic breast cancer patients, as well as the predictive biomarkers for outcome of treatment with pemetrexed-based regimens. METHODS: PubMed, Embase, OVID, and the Cochrane Library databases were searched from the beginning of each database without any limitations to the date of publication. Search terms were ''pemetrexed'' or ''LY231514'' or "Alimta", "metastatic breast cancer", and "advanced breast cancer". RESULTS: There were 15 studies (n = 1002) meeting our criteria for evaluation. Eight single-agent trials (n = 551) and seven using combinations with other agents (n = 451) were identified that evaluated pemetrexed for use in patients with metastatic breast cancer. Response rates to pemetrexed as a single agent varied from 8% to 31%, and with combination therapy have been reported to be between 15.8% and 55.7%. With routine supplementation of patients with folic acid, dexamethasone, and vitamin B12, the toxicity profile of these patients was mild, including dose-limiting neutropenia and thrombocytopenia, as well as lower grades of reversible hepatotoxicity and gastrointestinal toxicity. Expression of thymidylate synthase (TS) and other biomarkers are associated with the prognosis and sensitivity for pemetrexed in breast cancer. CONCLUSION: Pemetrexed has shown remarkable activity with acceptable toxicities for treatment of metastatic breast cancer patients. Translational research on pemetrexed in breast cancer identified biomarkers as well as additional genes important to its clinical activity and toxicity. Further research is needed to clarify the role of pemetrexed in breast cancer treatment in order to guide oncologists.