Optimization Of Cancer Treatment Through Overcoming Drug Resistance

Elshimali, Yahya; Wu, Yong; Khaddour, Husseina; Wu, Yanyuan; Grădinaru, Daniela; Sukhija, Hema; Chung, Seyung; Vadgama, Jaydutt V.

doi:10.31021/jcro.20181107

Cited by 19 publications

(14 citation statements)

References 129 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Adhesion molecules like L1CAM, which are involved in direct or indirect interactions between tumor cells and their microenvironment have been identified as potential targets for treatment of cancers [36,37], especially as L1CAM expression has been linked to augmented protection from apoptosis and increased chemoresistance in various cancer entities including retinoblastomas [21,23,38,39]. Besides, a multitude of studies showed that L1CAM is overexpressed in a variety of human cancers (for review see: [9]) and in nearly all cancers L1CAM expression was associated with poor prognosis, tumor progression and metastasis [9].…”

Section: Accepted Articlementioning

confidence: 99%

Role of L1CAM in retinoblastoma tumorigenesis: identification of novel therapeutic targets

et al. 2021

View full text Add to dashboard Cite

The study presented focuses on the role of the neuronal cell adhesion molecule L1CAM in retinoblastoma (RB), the most common malignant intraocular childhood tumor. L1CAM is differentially expressed in a variety of human cancers and has been suggested as a promising therapeutic target. We likewise observed differential expression patterns for L1CAM in RB cell lines and patient samples. The two proteases involved in ectodomain shedding of L1CAM (L1CAM sheddases; ADAM10 and ADAM17) were likewise differentially expressed in the RB cell lines investigated, and an involvement in L1CAM processing in RB cells could be verified. We also identified ezrin, galectin-3 and FGFb as L1CAM signaling target genes in RB cells. Lentiviral L1CAM knockdown induced apoptosis and reduced cell viability, proliferation, growth and colony formation capacity of RB cells, whereas L1CAM-overexpressing RB cells displayed the opposite effects. Chicken chorioallantoic membrane (CAM) assays revealed that L1CAM depletion decreases the tumorigenic and migration potential of RB cells in vivo. Moreover, L1CAM depletion decreased viability and tumor growth of etoposide-resistant RB cell lines upon etoposide treatment in vitro and in vivo. Thus, L1CAM and its processing sheddases are potential novel targets for future therapeutic RB approaches.

show abstract

Section: Accepted Articlementioning

confidence: 99%

Role of L1CAM in retinoblastoma tumorigenesis: identification of novel therapeutic targets

et al. 2021

View full text Add to dashboard Cite

show abstract

“…However, one major problem of cancer treatments, which also applies to BC, is the multidrug resistance coupled with the toxicity of some chemotherapeutics [25,26]. The emergence of drug resistance triggers the search for new drugs or drug adjuvants and, simultaneously, the need for a better understanding of the molecular mechanisms involved in drug resistance [27,28]. Accordingly, a search for compounds that are aimed at different therapeutic targets and/or that potentiate the existing established drugs with minimal, or at least decreased, toxicity towards normal cells has become a priority [29].…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic and Antiproliferative Effects of Preussin, a Hydroxypyrrolidine Derivative from the Marine Sponge-Associated Fungus Aspergillus candidus KUFA 0062, in a Panel of Breast Cancer Cell Lines and Using 2D and 3D Cultures

et al. 2019

View full text Add to dashboard Cite

Preussin, a hydroxyl pyrrolidine derivative isolated from the marine sponge-associated fungus Aspergillus candidus KUFA 0062, displayed anticancer effects in some cancer cell lines, including MCF7. Preussin was investigated for its cytotoxic and antiproliferative effects in breast cancer cell lines (MCF7, SKBR3, and MDA-MB-231), representatives of major breast cancers subtypes, and in a non-tumor cell line (MCF12A). Preussin was first tested in 2D (monolayer), and then in 3D (multicellular aggregates), cultures, using a multi-endpoint approach for cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), resazurin and lactate dehydrogenase (LDH)) and proliferative (5-bromo-2′-deoxyuridine (BrdU)) assays, as well as the analysis of cell morphology by optical/electron microscopy and immunocytochemistry for caspase-3 and ki67. Preussin affected cell viability and proliferation in 2D and 3D cultures in all cell lines tested. The results in the 3D culture showed the same tendency as in the 2D culture, however, cells in the 3D culture were less responsive. The effects were observed at different concentrations of preussin, depending on the cell line and assay method. Morphological study of preussin-exposed cells revealed cell death, which was confirmed by caspase-3 immunostaining. In view of the data, we recommend a multi-endpoint approach, including histological evaluation, in future assays with the tested 3D models. Our data showed cytotoxic and antiproliferative activities of preussin in breast cancer cell lines in 2D and 3D cultures, warranting further studies for its anticancer potential.

show abstract

“…Unfortunately, chemotherapeutic resistance to ADM has emerged as one of the essential reasons for treatment failure and death associated with breast cancer [4,5]. Significant efforts should be undertaken to resolve the molecular mechanisms that lead to ADM resistance, and identified novel biomarkers that can predict treatment response and overcome ADM resistance Placenta-specific 8 (PLAC8, Onzin) was firstly identified via genome-wide gene expression analysis in the placenta, and PLAC8 protein was restricted to the spongiotrophoblast layer of the mouse placenta [6,7].…”

Section: Backgroudmentioning

confidence: 99%

PLAC8 promotes adriamycin resistance via blocking autophagy in breast cancer

chen¹,

Jia

Mao

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Adriamycin (ADM) is currently one of the most effective chemotherapeutic agents in breast cancer treatment. However, growing resistance to ADM can lead to treatment failure and poor outcome. The underlying molecular mechanisms in ADM resistance in breast cancer remains unclear. PLAC8 is reported as a novel highly-conserved protein and functions as an oncogene or tumor suppressor in various tumors. Methods Here, we analyzed the expression profile of PLAC8 in breast cancer tissues and breast cancer cell lines, and explored the correlation of PLAC8 expression levels with patients’ outcomes and ADM response. One ADM resistant MCF-7 breast cancer cell (MCF-7/ADM) and its parental cell was used as in vitro models to identify the underlying mechanism of PLAC8 and ADM resistance. Breast cancer cells were transfected with PLAC8 knockdown and overexpression vectors, and MTT and colony formation assays were performed to test the cell response to ADM. Then, we tested the effect of PLAC8 on autophagy pathway by flow cytometry and immunofluorescence analysis, and the change of main autophagy-correlated factors expressions: LC3 and p62. Next, combining treatment of autophagy inhibitor/inducer and PLAC8 downregulation/upregulation revealed the participation of PLAC8 in autophagy pathway to synergistically regulate ADM resistance in breast cancer. Results Here, higher PLAC8 expression was correlated with poorer outcome and aggressive phenotype in breast cancer, and breast cancer patients with higher PLAC8 expression showed potential ADM resistance. PLAC8 expression level was also significantly elevated in ADM resistant MCF-7 breast cancer cells (MCF-7/ADM), compared to parental MCF-7 cells. In vitro experiments further confirmed that PLAC8 inhibition by siRNA or enforced overexpression by infecting pcDNA3.1(C)-PLAC8 plasmid correspondingly decreased or increased the ADM resistance. Subsequently, we demonstrated that ectopic PLAC8 expression in MCF-7/ADM cell blocked the accumulation of the autophagy-associated protein LC3II, and resulted in cellular accumulation of p62. Rapamycin-triggered autophagy significantly increased cell response to ADM, while the autophagy inhibitor 3-MA enhanced ADM resistance. Actually, 3-MA and PLAC8 could synergistically enhance ADM resistance via blocking the autophagy process. Additionally, the downregulation of p62 by siRNA attenuated the activation of autophagy and PLAC8 expression in breast cancer cells. Conclusion Our findings suggest that PLAC8, through participation of p62, inhibits autophagy and consequently results in ADM resistance in breast cancer. PLAC8/p62/autophagy pathway may act as novel therapeutic targets in breast cancer treatment and has potential clinical application in overcoming ADM resistance.

show abstract

Optimization Of Cancer Treatment Through Overcoming Drug Resistance

Cited by 19 publications

References 129 publications

Role of L1CAM in retinoblastoma tumorigenesis: identification of novel therapeutic targets

Role of L1CAM in retinoblastoma tumorigenesis: identification of novel therapeutic targets

Cytotoxic and Antiproliferative Effects of Preussin, a Hydroxypyrrolidine Derivative from the Marine Sponge-Associated Fungus Aspergillus candidus KUFA 0062, in a Panel of Breast Cancer Cell Lines and Using 2D and 3D Cultures

PLAC8 promotes adriamycin resistance via blocking autophagy in breast cancer

Contact Info

Product

Resources

About