Recent Approaches Encompassing the Phenotypic Cell Heterogeneity for Anticancer Drug Efficacy Evaluation

Stulpinas, Aurimas; Imbrasaitė, Aušra; Krestnikova, Natalija; Kalvelytė, Audronė

doi:10.5772/intechopen.89395

Cited by 2 publications

(3 citation statements)

References 246 publications

(272 reference statements)

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“…A variety of non-genetic mechanisms of cell resistance influencing drug responses have been described in many cancers. Usually, phenotype switching, cell dynamic state, and extracellular contacts, along with the identification of molecular mechanisms, are assessed during the evaluation of drug effectiveness ( 1 ). We rely on the opinion that cell state-specific therapy is one of the essential approaches in modern cancer treatment ( 29 ), where cell fate may be determined by the activity of MEK/ERK and PI3K/AKT signaling pathways, influenced by cell-specific intrinsic and extrinsic sources.…”

Section: Discussionmentioning

confidence: 99%

“…They encompass various aspects of the phenomenon, such as resistance to conventional and targeted drugs, hormone therapy, and immune oncology agents in various types of tumors. Various causes, modes, and mechanisms of resistance, ranging from genetic to phenotypic, have been described in many reviews, including ours (1). There is no doubt that, in addition to genetic changes, the acquisition of non-genetic causes of resistance determines the outcome of cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

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Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models

et al. 2023

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There is no doubt that cell signaling manipulation is a key strategy for anticancer therapy. Furthermore, cell state determines drug response. Thus, establishing the relationship between cell state and therapeutic sensitivity is essential for the development of cancer therapies. In the era of personalized medicine, the use of patient-derived ex vivo cell models is a promising approach in the translation of key research findings into clinics. Here, we were focused on the non-oncogene dependencies of cell resistance to anticancer treatments. Signaling-related mechanisms of response to inhibitors of MEK/ERK and PI3K/AKT pathways (regulators of key cellular functions) were investigated using a panel of patients’ lung tumor-derived cell lines with various stemness- and EMT-related markers, varying degrees of ERK1/2 and AKT phosphorylation, and response to anticancer treatment. The study of interactions between kinases was the goal of our research. Although MEK/ERK and PI3K/AKT interactions are thought to be cell line-specific, where oncogenic mutations have a decisive role, we demonstrated negative feedback loops between MEK/ERK and PI3K/AKT signaling pathways in all cell lines studied, regardless of genotype and phenotype differences. Our work showed that various and distinct inhibitors of ERK signaling – selumetinib, trametinib, and SCH772984 – increased AKT phosphorylation, and conversely, inhibitors of AKT – capivasertib, idelalisib, and AKT inhibitor VIII – increased ERK phosphorylation in both control and cisplatin-treated cells. Interaction between kinases, however, was dependent on cellular state. The feedback between ERK and AKT was attenuated by the focal adhesion kinase inhibitor PF573228, and in cells grown in suspension, showing the possible role of extracellular contacts in the regulation of crosstalk between kinases. Moreover, studies have shown that the interplay between MEK/ERK and PI3K/AKT signaling pathways may be dependent on the strength of the chemotherapeutic stimulus. The study highlights the importance of spatial location of the cells and the strength of the treatment during anticancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models

et al. 2023

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“…It has been accepted that the heterogeneity of cancer population crucially influences the relatively low success rate of current anticancer drugs [ 11 ]. The subpopulation of cancer stem-like cells (CSCs) within tumor tissue is imbued with stemness features of self-renewal and multilineage differentiation, thus allowing tumor initiation from the remaining CSCs after chemotherapy [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Stemness-Suppressive Effect of Bibenzyl from Dendrobium ellipsophyllum in Human Lung Cancer Stem-Like Cells

Taweecheep

Khine

Hlosrichok

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Cancer stem-like cells (CSCs) are key mediators driving tumor initiation, metastasis, therapeutic failure, and subsequent cancer relapse. Thus, targeting CSCs has recently emerged as a potential strategy to improve chemotherapy. In this study, the anticancer activity and stemness-regulating capacity of 4,5,4′-trihydroxy-3,3′-dimethoxybibenzyl (TDB), a bibenzyl extracted from Dendrobium ellipsophyllum, are revealed in CSCs of various human lung cancer cells. Culture with TDB (5–10 μM) strongly abolished tumor-initiating cells in lung cancer H460, H23, and A549 cells in both anchorage-dependent and anchorage-independent colony formation assays. Through the 3D single-spheroid formation model, attenuation of self-renewal capacity was observed in CSC-enriched populations treated with 1–10 μM TDB for 7 days. Flow cytometry analysis confirmed the attenuation of %cell overexpressing CD133, a CSC biomarker, in TDB-treated lung cancer spheroids. TDB at 5–10 μM remarkably suppressed regulatory signals of p-Akt/Akt, p-GSK3β/GSK3β, and β-catenin corresponding to the downregulated mRNA level of stemness transcription factors including Nanog, Oct4, and Sox2. Moreover, the antiapoptosis Bcl-2 and Mcl-1 proteins, which are downstream molecules of Akt signaling, were evidently decreased in CSC-enriched spheroids after culture with TDB (1–10 μM) for 24 h. Interestingly, the diminution of Akt expression by specific siAkt effectively reversed suppressive activity of TDB targeting on the CSC phenotype in human lung cancer cells. These findings provide promising evidence of the inhibitory effect of TDB against lung CSCs via suppression of Akt/GSK3β/β-catenin cascade and related proteins, which would facilitate the development of this bibenzyl natural compound as a novel CSC-targeted therapeutic approach for lung cancer treatment.

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Recent Approaches Encompassing the Phenotypic Cell Heterogeneity for Anticancer Drug Efficacy Evaluation

Cited by 2 publications

References 246 publications

Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models

Crosstalk between protein kinases AKT and ERK1/2 in human lung tumor-derived cell models

Stemness-Suppressive Effect of Bibenzyl from Dendrobium ellipsophyllum in Human Lung Cancer Stem-Like Cells

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