Targeting cancer stem cell pathways for lung cancer therapy

Liu, Mingxin; Wu, Hong; Xu, Chuan

doi:10.1097/cco.0000000000000912

Cited by 7 publications

(3 citation statements)

References 73 publications

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“…Numerous treatment approaches have been explored for NSCLCs, with a particular emphasis on targeting CSCs and modulating self-renewal pathways as a key strategy in the treatment of lung cancer [40]. Extensive evidence suggests that the presence of self-renewal capacity and the overexpression of stem cell transcription factors have been associated with accelerated cancer cell growth, increased invasion, metastasis, drug resistance, and unfavorable clinical outcomes [41][42][43].…”

Section: Discussionmentioning

confidence: 99%

Simplified Synthesis of Renieramycin T Derivatives to Target Cancer Stem Cells via β-Catenin Proteasomal Degradation in Human Lung Cancer

Ei,

Racha,

Yokoya

et al. 2023

Marine Drugs

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Cancer stem cells (CSCs) found within cancer tissue play a pivotal role in its resistance to therapy and its potential to metastasize, contributing to elevated mortality rates among patients. Significant strides in understanding the molecular foundations of CSCs have led to preclinical investigations and clinical trials focused on CSC regulator β-catenin signaling targeted interventions in malignancies. As part of the ongoing advancements in marine-organism-derived compound development, it was observed that among the six analogs of Renieramycin T (RT), a potential lead alkaloid from the blue sponge Xestospongia sp., the compound DH_32, displayed the most robust anti-cancer activity in lung cancer A549, H23, and H292 cells. In various lung cancer cell lines, DH_32 exhibited the highest efficacy, with IC50 values of 4.06 ± 0.24 μM, 2.07 ± 0.11 μM, and 1.46 ± 0.06 μM in A549, H23, and H292 cells, respectively. In contrast, parental RT compounds had IC50 values of 5.76 ± 0.23 μM, 2.93 ± 0.07 μM, and 1.52 ± 0.05 μM in the same order. Furthermore, at a dosage of 25 nM, DH_32 showed a stronger ability to inhibit colony formation compared to the lead compound, RT. DH_32 was capable of inducing apoptosis in lung cancer cells, as demonstrated by increased PARP cleavage and reduced levels of the proapoptotic protein Bcl2. Our discovery confirms that DH_32 treatment of lung cancer cells led to a reduced level of CD133, which is associated with the suppression of stem-cell-related transcription factors like OCT4. Moreover, DH_32 significantly suppressed the ability of tumor spheroids to form compared to the original RT compound. Additionally, DH_32 inhibited CSCs by promoting the degradation of β-catenin through ubiquitin–proteasomal pathways. In computational molecular docking, a high-affinity interaction was observed between DH_32 (grid score = −35.559 kcal/mol) and β-catenin, indicating a stronger binding interaction compared to the reference compound R9Q (grid score = −29.044 kcal/mol). In summary, DH_32, a newly developed derivative of the right-half analog of RT, effectively inhibited the initiation of lung cancer spheroids and the self-renewal of lung cancer cells through the upstream process of β-catenin ubiquitin–proteasomal degradation.

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Section: Discussionmentioning

confidence: 99%

Simplified Synthesis of Renieramycin T Derivatives to Target Cancer Stem Cells via β-Catenin Proteasomal Degradation in Human Lung Cancer

Ei,

Racha,

Yokoya

et al. 2023

Marine Drugs

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“…First, nanomaterials can leverage the enhanced permeability and retention (EPR) effect to accumulate and be selectively retained within tumor tissues. − Second, nanomaterial surfaces can be facilely functionalized with proteins, peptides, and biomolecules to enhance targeting precision. − Third, nanomaterials provide protection for encapsulated drugs, genes, and therapeutic agents, shielding them from degradation in physiologically complex microenvironments . Furthermore, stimuli-responsive nanomaterials have been developed that reduce systemic drug toxicity through triggered release in response to internal or external cues. , Notably, the diversification of nanomaterial-based delivery systems continues to broaden the range of applications in cancer treatment while propelling clinical translation. , Numerous research interests have been directed toward developing clinical agents to target CSCs, with the application of nanomaterials for precision CSCs targeting becoming a key topic. − However, there remains a lack of systematic reviews comprehensively examining the utility of diverse nanomaterial types across the breadth of recently developed CSC-targeted strategies, including bioengineered nanostructures and advanced delivery platforms.…”

Section: Introductionmentioning

confidence: 99%

Sniping Cancer Stem Cells with Nanomaterials

Wang,

Guo,

Yang

et al. 2023

ACS Nano

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“…CSCs possess these properties via signaling pathways, including the Notch, WNT, Hedgehog, and Hippo pathways ( 14 ). While agents that target CSCs in all cancer types, including lung cancer, are not currently available in clinical settings, previous studies reported the development of drugs that target CSCs in NSCLC ( 14 , 16 - 19 ). For example, inhibitory antibodies against delta-like ligands 3 and 4, which are involved in the Notch signaling pathway, have been developed as novel drugs targeting CSCs and are being used in phase I and II clinical trials for NSCLC and small cell lung cancer (SCLC) patients ( 16 , 17 ).…”

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confidence: 99%