Mecanismos moleculares de la farmacorresistencia en el cáncer de mama y posibles estrategias para superar la resistencia: Una revisión de la literatura / Molecular mechanisms of drug resistance in breast cancer and potential strategies for overcoming resistance: A literature review

El cáncer de mama es la causa más común de muerte por cáncer en el mundo, y la resistencia a los medicamentos es una de las barreras más importantes para el éxito de la terapia de la enfermedad. Es fundamental tener una comprensión sólida de los procesos moleculares que impulsan la resistencia al tratamiento en el cáncer de mama para diseñar terapias dirigidas con el potencial de superar esta resistencia. Estos mecanismos son complejos y multifacéticos e incluyen la activación de vías de señalización que promueven la supervivencia y proliferación celular, la regulación positiva de las bombas de salida de fármacos, la aparición de células madre cancerosas y cambios genéticos y epigenéticos. Esta revisión de la literatura brinda una descripción general de estos mecanismos y analiza las posibles estrategias para superar la resistencia a los medicamentos en el cáncer de mama, incluido el uso de terapias dirigidas que se dirigen específicamente a las vías y los mecanismos involucrados en la resistencia a los medicamentos. La revisión también destaca la necesidad de más investigación para identificar estrategias efectivas para superar la resistencia a los medicamentos y mejorar los resultados del tratamiento en pacientes con cáncer de mama.

Breast cancer is the most common cause of death from cancer in the world, and drug resistance is one of the most significant barriers to successful therapy for the disease. It is critical to have a solid understanding of the molecular processes driving treatment resistance in breast cancer to design targeted therapies with the potential to overcome this resistance. These complex and multifaceted mechanisms include the activation of signaling pathways that promote cell survival and proliferation, the upregulation of drug efflux pumps, the emergence of cancer stem cells, and genetic and epigenetic changes. This literature review provides an overview of these mechanisms. It discusses potential strategies for overcoming drug resistance in breast cancer, including targeted therapies that specifically target the pathways and mechanisms involved in drug resistance. The review also highlights the need for further research to identify effective strategies for overcoming drug resistance and improving treatment outcomes in breast cancer patients.

In vitro antioxidant, anti-inflammatory, and anticancer activities of mixture Thai medicinal plants.

BACKGROUND: The phytochemical study of medicinal plants is rapidly gaining popularity with many pharmacologic effects. This study aims to determine the antioxidant capacity as well as anticancer and antimigration activities of Clear belongs Plus extract (CBL-P) which consisted of five medicinal plants namely, Alpinia galanga, Piper nigrum, Citrus aurantifolia, Tiliacora triandra, and Cannabis sativa on human colon cancer cells SW620 and HCT116 cell lines, and human non-small cell lung cancer cells A549 and NCI-H460 cell lines. METHODS: In this study the dried-plant powder was extracted using 90% ethanol. Additionally, CBL-P was studied antioxidative activity via DPPH and ABTS assays and anti-inflammatory activities using nitric oxide assay using Griess reaction. Antiproliferation and antimigration of CBL-P were investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and scratch assay. RESULTS: The results showed that CBL-P had potent antiproliferative activity with IC50 values in a concentration- and time-dependent manners for all four cell lines. CBL-P also possessed potent antimigration activity against all studied cancer cells. CBL-P demonstrated antimigration activity on four different types of cancer cells (A549, NCI-H460, HCT116, and SW620) after 48 h of incubation, with the greatest effect seen at the highest concentration tested (15 µg/mL) in A549 cells (10.23% of wound closure) and NCI-H460 cells (9.16% of wound closure). CBL-P was also effective in reducing migration in HCT116 and SW620 cells, with a range of closure area from 10-50%. In addition, CBL-P had antioxidant activity with IC50 values of 8.549 ± 0.241 mg/mL and 2.673 ± 0.437 mg/mL for DPPH and ABTS assays, respectively. CBL-P also showed anti-inflammatory activity with the best inhibitory activity on NO production at a concentration of 40 µg/mL. CONCLUSION: In conclusion, the mixture extract possessed antioxidant and anti-inflammatory activity. Furthermore, the mixture plant extract significantly exhibited antiproliferative and antimigration activities on SW620, HCT116, A549, and NCI-H460 cells (P ≤ 0.05). Taken together, our results suggest that medicinal plants may have synergistic effects that could potentially enhance the effectiveness of cancer treatment when used as adjuvants. These findings provide a solid scientific foundation for future efforts to explore the mechanism of action.

1'-Acetoxychavicol Acetate from Alpinia galanga Represses Proliferation and Invasion, and Induces Apoptosis via HER2-signaling in Endocrine-Resistant Breast Cancer Cells.

Estrogen receptor-positive breast cancer patients have a good prognosis, but 30% of these patients will experience recurrence due to the development of resistance through various signaling pathways. This study aimed to evaluate the mode of anticancer effects of 1'-acetoxychavicol acetate, which is isolated from the rhizomes of Alpinia galanga in estrogen receptor positive (MCF7) human epidermal growth factor receptor 2-overexpressed (MCF7/HER2), and endocrine-resistant breast cancer cells (MCF7/LCC2 and MCF7/LCC9). 1'-Acetoxychavicol acetate showed antiproliferation in a concentration- and time-dependent fashion and had higher potency in human epidermal growth factor receptor 2-overexpressed cell lines. This was associated with down-regulation of human epidermal growth factor receptor 2, pERK1/2, pAKT, estrogen receptor coactivator, cyclin D1, and MYC proto-oncogene while in vivo and significant reduction in the tumor mass of 1'-acetoxychavicol acetate-treated zebrafish-engrafted breast cancer groups. The anti-invasive effects of 1'-acetoxychavicol acetate were confirmed in vitro by the matrigel invasion assay and with down-regulation of C - X-C chemokine receptor type 4, urokinase plasminogen activator, vascular endothelial growth factor, and basic fibroblast growth factor 2 genes. The down-regulation of urokinase plasminogen activator and fibroblast growth factor 2 proteins was also validated by molecular docking analysis. Moreover, 1'-acetoxychavicol acetate-treated cells exhibited lower expression levels of the anti-apoptotic Bcl-2 and Mcl-1 proteins in addition to enhanced stress-activated kinases/c-Jun N-terminal kinase 1/2 and poly-ADP ribose polymerase cleavage, indicating apoptotic cell induction by 1'-acetoxychavicol acetate. Moreover, 1'-acetoxychavicol acetate had higher potency in human epidermal growth factor receptor 2-overexpressed cell lines regarding its inhibition on human epidermal growth factor receptor 2, pAKT, pERK1/2, PSer118, and PSer167-ERα proteins. Our findings suggest 1'-acetoxychavicol acetate mediates its anti-cancer effects via human epidermal growth factor receptor 2 signaling pathway.

NADPH: Quinone oxidoreductase 1 (NQO1) mediated anti-cancer effects of plumbagin in endocrine resistant MCF7 breast cancer cells.

BACKGROUND: PLB is a natural naphthoquinone compound isolated from the roots of Plumbago indica plant. Our previous study reported the inhibitory effect of Plumbagin (PLB) on human endocrine resistant breast cancer cell growth and cell invasion. HYPOTHESIS/PURPOSE: Since PLB is a naphthoquinone compound, it can be reduced by the cytosolic NADPH: quinone oxidoreductase 1 (NQO1) enzyme. NQO1 expression is upregulated in various types of aggressive cancer including breast cancer. This study investigated the impact of NQO1 on anti-cancer effects of PLB in endocrine-resistant breast cancer cells. STUDY DESIGN: This study was an in vitro study using ER-positive cell line (MCF7) and endocrine-resistant cell lines (MCF7/LCC2 and MCF7/LCC9 cells). METHODS: The roles of NQO1 in anti-cancer activity of PLB were investigated by using NQO1 knockdown cells, NQO1 inhibitor and NQO1 overexpressed cells. To study the impact of NQO1 on the effects of PLB on cell viability, apoptosis, invasion and generation of ROS, the following assays were used: MTT assays, annexin V-PE/7-ADD staining flow cytometry, matrigel invasion assays and DCFHDA assays. To study the mechanism of how NQO1 mediated PLB effects in tamoxifen response and apoptosis, we assessed the levels of mRNA expression by using qRT-PCR. RESULTS: 1. In this study, NQO1 was upregulated in endocrine-resistant cells. 2. PLB did not change the expression of NQO1 but it was able to increase NQO1 activity. 3. The inhibitory effects of PLB on cell proliferation, cell invasion and expression of tamoxifen resistant gene were attenuated in NQO1 knockdown cells or in the presence of NQO1 inhibitor. 4. The effects of PLB to induce apoptosis and generate ROS were also decreased when NQO1 activity was inhibited or when the NQO1 expression was reduced. 5. The anti-cancer effects of PLB increased when NQO1 was upregulated. CONCLUSION: The effects of PLB in endocrine-resistant breast cancer cells is dependent on NQO1's activity.

Ethoxy mansonone G as an anticancer agent in estrogen receptor-positive and endocrine-resistant breast cancer.

OBJECTIVES: To study anticancer effects, underlying mechanism and safety of ethoxy mansonone G (EMG) which is the potent derivative of mansonone G (MG) in breast cancer cells. METHODS: Anticancer, antimigration, anti-invasion effects and anchorage-independent growth were investigated by MTT, scratch, matrigel invasion and soft agar assays. Estrogen receptor (ER)-targeted genes and endocrine-resistant genes were assessed by RT-PCR and Western blot. KEY FINDINGS: Ethoxy mansonone G is the most potent MG derivative and has anticancer effects in ER-positive, endocrine-resistant and ER-negative breast cancer cells. Our results demonstrated that EMG can significantly inhibit estrogen-induced cell proliferation and the expression of ER-targeted genes in ER-positive breast cancer cells, suggesting the anti-estrogenic property of EMG which is consisting with the virtual molecular docking that EMG could possibly bind to the ERα. Moreover, EMG has synergistic effect with tamoxifen in endocrine-resistant cells. EMG also inhibited cell proliferation, invasion and anchorage-independent growth by reducing expression of genes involved in endocrine resistance and invasive factors during the metastatic process. CONCLUSION: Ethoxy mansonone G has an anticancer effect in breast cancer cells and is possible to use as a therapeutic agent in patients with breast cancer.