Overcoming the acquired resistance to gefitinib in lung cancer brain metastasis in vitro and in vivo

Liu, Zhongwei; Shah, Neal; Marshall, Kent; Sprowls, Samuel A.; Saralkar, Pushkar; Mohammad, Afroz S.; Blethen, Kathryn E.; Arsiwala, Tasneem; Fladeland, Ross; Lockman, Paul R.; Gao, Weimin

doi:10.1007/s00204-021-03147-4

Cited by 8 publications

(4 citation statements)

References 64 publications

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“…Bcl-xl was not remarkably upregulated in the model group compared to the control group, which may be related to the cell line used in this study. For example, in the lung cancer brain metastasis model constructed by the human NSCLC PC-9 cell line, Bcl-2 was also significantly upregulated, while Bcl-xl is not remarkably upregulated ( Liu et al, 2021 ), suggesting that the expression of apoptosis-related proteins depends on the cancer cell lines. Autophagy is usually hijacked by cancer cells to survive the energy crisis caused by rapid proliferation and the cellular stress caused by anticancer drugs.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the Effects and Mechanisms of Yi-Fei-San-Jie-pill on Non-Small Cell Lung Cancer With Integrating Network Target Analysis and Experimental Validation

Yang

Guo

et al. 2022

Front. Pharmacol.

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Non-small cell lung cancer (NSCLC), which accounts for 85% of lung cancer cases, calls for better therapy. Yi-Fei-San-Jie-pill (YFSJ), a well-applicated traditional Chinese medicine formula, was reported to be effective in the treatment of NSCLC. However, its anti-tumor mechanism still needs to be fully elucidated. Herein, a reliable preclinical orthotopic but not subcutaneous model of NSCLC in mice was established to evaluate the anti-cancer properties and further validate the mechanisms of YFSJ. A bioinformatic analysis was executed to identify the potential targets and key pathways of YFSJ on NSCLC. In detail, the anti-tumor effect of YFSJ and the autophagy inhibitor 3-MA was evaluated according to the tumor fluorescence value and comparison of different groups’ survival times. As a result, YFSJ markedly decreased tumor size and prolonged survival time in contrast with those in the orthotopic model group (p < 0.05), and it also significantly regulated the protein expression levels of apoptosis- and autophagy-related proteins. In conclusion, this study provides convincing evidence that YFSJ could inhibit the growth of tumors and prolong the survival time of tumor-bearing mice based on the NSCLC orthotopic model, and its anti-tumor effect was closely associated with the promotion of apoptosis and interference of autophagy coupled with regulation of immune infiltration.

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Section: Discussionmentioning

confidence: 99%

Deciphering the Effects and Mechanisms of Yi-Fei-San-Jie-pill on Non-Small Cell Lung Cancer With Integrating Network Target Analysis and Experimental Validation

Yang

Guo

et al. 2022

Front. Pharmacol.

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“…Western blot was used to examine the protein expression in HCC827 and HCC827GR or the six treatment groups of HCC827GR as previously described. 35,36 The intensities for all the bands of interest were quantified using ImageJ software and normalized using the housekeeping gene, tubulin.…”

Section: Western Blotmentioning

confidence: 99%

Caffeic acid phenethyl ester surmounts acquired resistance of AZD9291 in non‐small cell lung cancer cells

2023

Self Cite

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Epithelial growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) are the first‐line therapy for EGFR mutated non‐small cell lung cancer (NSCLC); however, resistance rapidly develops. The objective of this study was therefore to establish and characterize a gefitinib resistant NSCLC line (HCC827GR) and evaluate the therapeutic effects of natural products in combination with third‐generation EGFR‐TKI, AZD9291. The IC50 of gefitinib and AZD9291 in HCC827GR were significantly higher than those of HCC827 (p < 0.05). Furthermore, anchorage‐independent colony assay indicated that HCC827GR cells were more aggressive than their predecessors. This was reflected by the gene/protein expression changes observed in HCC827GR versus HCC827 profiled by cancer drug resistance real‐time polymerase chain reaction (RT‐PCR) array and Western blot. Three natural products were screened and caffeic acid phenethyl ester (CAPE) exhibited the most significant combinative cytotoxic effect with AZD9291. Specifically, flow cytometry revealed that AZD9291 + CAPE considerably increased the fraction of cell in pre‐G1 of the cell cycle and caspase‐Glo3/7 assay showed a dramatic increase in apoptosis when compared to AZD9291 alone. Furthermore, Western blot showed significant downregulation of p‐EGFR/p‐AKT in HCC827GR cells treated with AZD9291 + CAPE as compared to AZD9291. Moreover, it is evident that AZD9291 + CAPE specifically resulted in a marked reduction in the protein expressions of the cell‐proliferation‐related genes p21, cyclin D1, and survivin. Finally, refined RT‐PCR/Western blot data indicated that AZD9291 + CAPE may at least partially exert its synergistic effects via the PLK2 pathway. Together, these results suggest that CAPE is a clinically relevant compound to aid AZD9291 in treating EGFR‐TKI resistant cells through modulating critical genes/proteins involved in cancer resistance/therapy.

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“…This result suggests the potential of combining venetoclax with epigenetic therapy in NSCLC. For brain metastasis in NSCLC, the EGFR-tyrosine kinase inhibitor gefitinib combined with venetoclax or navitoclax showed appreciable synergistic effects against NSCLC tumors and was expected to overcome gefitinib-induced resistance [149]. Moreover, dynamic BH3 profiling (DBP) has been applied as a precision medicine tool to evaluate the efficacy of BHC mimetics in NSCLC, and navitoclax combined with etoposide significantly alleviated the tumor burden [150].…”

Section: Lung Cancermentioning

confidence: 99%

Current Advances and Future Strategies for BCL-2 Inhibitors: Potent Weapons against Cancers

Xu,

Dong,

Huang

et al. 2023

Cancers

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Targeting the intrinsic apoptotic pathway regulated by B-cell lymphoma-2 (BCL-2) antiapoptotic proteins can overcome the evasion of apoptosis in cancer cells. BCL-2 inhibitors have evolved into an important means of treating cancers by inducing tumor cell apoptosis. As the most extensively investigated BCL-2 inhibitor, venetoclax is highly selective for BCL-2 and can effectively inhibit tumor survival. Its emergence and development have significantly influenced the therapeutic landscape of hematological malignancies, especially in chronic lymphocytic leukemia and acute myeloid leukemia, in which it has been clearly incorporated into the recommended treatment regimens. In addition, the considerable efficacy of venetoclax in combination with other agents has been demonstrated in relapsed and refractory multiple myeloma and certain lymphomas. Although venetoclax plays a prominent antitumor role in preclinical experiments and clinical trials, large individual differences in treatment outcomes have been characterized in real-world patient populations, and reduced drug sensitivity will lead to disease recurrence or progression. The therapeutic efficacy may vary widely in patients with different molecular characteristics, and key genetic mutations potentially result in differential sensitivities to venetoclax. The identification and validation of more novel biomarkers are required to accurately predict the effectiveness of BCL-2 inhibition therapy. Furthermore, we summarize the recent research progress relating to the use of BCL-2 inhibitors in solid tumor treatment and demonstrate that a wealth of preclinical models have shown promising results through combination therapies. The applications of venetoclax in solid tumors warrant further clinical investigation to define its prospects.

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Overcoming the acquired resistance to gefitinib in lung cancer brain metastasis in vitro and in vivo

Cited by 8 publications

References 64 publications

Deciphering the Effects and Mechanisms of Yi-Fei-San-Jie-pill on Non-Small Cell Lung Cancer With Integrating Network Target Analysis and Experimental Validation

Deciphering the Effects and Mechanisms of Yi-Fei-San-Jie-pill on Non-Small Cell Lung Cancer With Integrating Network Target Analysis and Experimental Validation

Caffeic acid phenethyl ester surmounts acquired resistance of AZD9291 in non‐small cell lung cancer cells

Current Advances and Future Strategies for BCL-2 Inhibitors: Potent Weapons against Cancers

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