Chlorpromazine cooperatively induces apoptosis with tyrosine kinase inhibitors in EGFR-mutated lung cancer cell lines and restores the sensitivity to gefitinib in T790M-harboring resistant cells

Fujiwara, Ryosuke; Taniguchi, Yasuhiro; Rai, Shinya; Iwata, Yoshio; Fujii, Atsuko; Fujimoto, Ko; Kumode, Takahiro; Serizawa, Kentaro; Morita, Yasuyoshi; Espinoza, J. Luis; Tanaka, Hirokazu; Hanamoto, Hitoshi; Matsumura, Itaru

doi:10.1016/j.bbrc.2022.08.010

Cited by 8 publications

(3 citation statements)

References 36 publications

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“…According to the results of our research, apoptosis of hepatocytes significantly increased when Clopromazine was administered for 30 days at a dose of 7, 14, 21, and 28 mg/kg, and when the drug was used for 60 days at a dose of 3.5-21 mg/kg. The obtained data correspond to the data of the literature [7,8,15], according to which Chlopromazine, together with tyrosine kinase inhibitors, increases the apoptosis of tumor cells. Chlorpromazine also acts as a destabilizer of lysosomal membranes, which also promotes apoptosis [17].…”

Section: Discussionsupporting

confidence: 87%

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Investigation of nuclear DNA content and cell cycle phases in rat liver cells under chlorpromazine administration

Rykalo,

Baylo

2023

Rep. of Morph.

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Hepatotoxicity of antipsychotic drugs remains an urgent problem of modern medicine. Therefore, the purpose of the study was to investigate the nuclear DNA content and cell cycle phases of rat liver cells under Сhlorpromazine administration at doses ranging from 3.5 mg/kg to 28 mg/kg for 30 and 60 days. The study was conducted on 60 sexually mature female rats. Chlorpromazine was administered once daily for 30 and 60 days at doses of 3.5 mg/kg, 7 mg/kg, 14 mg/kg, 21 mg/kg and 28 mg/kg. The DNA content in the nuclei of rat liver cells was determined by flow cytometry. Cytological analysis of cells was performed using FloMax software (Partec, Germany), where the percentage of nuclei in the G0G1 interval of the cell cycle, in the S phase, G2M interval, and the apoptosis index – SUB-G0G1 area on DNA histograms were determined. Statistical processing of the results was performed using the Mann-Whitney U test. The results of the study showed that Сhlorpromazine has a dose-dependent hepatotoxic effect: with an increase in the dose of this drug in rats from 7 to 28 mg/kg, the percentage of fragmented nuclei in liver tissue significantly increased, which is a sign of hepatocyte death by apoptosis. It was found that Сhlorpromazine at a dose of 3.5 mg/kg did not increase hepatocyte apoptosis, while at a dose of 21 and 28 mg/kg the drug showed the highest hepatotoxicity, increasing the level of apoptosis by 1.9 and 2.1 (p˂0.05) times, respectively. The hepatotoxic effect is enhanced by the use of Сhlorpromazine for 60 days, which is manifested in a significant increase in hepatocyte nuclear DNA fragmentation, which, in our opinion, should be taken into account when conducting long-term therapy in patients.

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Section: Discussionsupporting

confidence: 87%

“…According to the authors, this proapoptotic therapeutic potential of Chlorpromazine can be used in complex therapy of various types of neoplasms [5,7,14,23].…”

Section: Discussionmentioning

confidence: 99%

Investigation of nuclear DNA content and cell cycle phases in rat liver cells under chlorpromazine administration

Rykalo,

Baylo

2023

Rep. of Morph.

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“…mTOR inhibitors (notably RAD001, an oral rapamycin derivative) have been approved by the US Food and Drug Administration (FDA) for wider use in antitumor clinical treatment, providing more treatment options for patients with pancreatic neuroendocrine tumors (PNETs), estrogen receptor + + HER2 − breast cancer and other solid tumors ( 24 ). A study has shown that RAD001 promotes the death of T790M + NSCLC cells ( 25 ), suggesting that RAD001 is a potential treatment strategy for EGFR-TKI resistant tumors. In addition, inhibition of mTOR overcomes lapatinib resistance by inducing ferroptosis in NSCLC ( 26 ), suggesting that the regulation of mTOR may promote ferroptosis and overcome EGFR-TKI resistance.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of targeting the mTOR pathway to regulate ferroptosis in NSCLC with different EGFR mutations

Wu,

Zhong,

Wei

et al. 2024

Oncol Lett

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Patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations can be treated with EGFR-tyrosine kinase inhibitors (TKIs). Although EGFR-TKI-targeted drugs bring survival promotion in patients with EGFR mutations, drug resistance is inevitable, so it is urgent to explore new treatments to overcome drug resistance. In addition, wild-type EGFR lacks targeted drugs, and new targeted therapies need to be explored. Ferroptosis is a key research direction for overcoming drug resistance. However, the role and mechanism of regulating ferroptosis in different EGFR-mutant NSCLC types remains unclear. In the present study, H1975 (EGFR T790M/L858R mutant), A549 (EGFR wild-type) and H3255 (EGFR L858R mutant) NSCLC cell lines were used. The expression of ferroptosis markers in these cell lines was detected using western blotting and reverse transcription-quantitative PCR. Cell viability was determined using the MTT assay and reactive oxygen species (ROS) levels were measured using flow cytometry. The results showed that, compared with EGFR wild-type/sensitive mutant cells, EGFR-resistant mutant cells were more sensitive to the ferroptosis inducer, erastin. Furthermore, the mammalian target of rapamycin (mTOR) inhibitor, everolimus (RAD001), induced cell death in all three cell lines in a dose-dependent manner. The ferroptosis inhibitor, ferrostatin-1, could reverse cell death in EGFR-resistant mutant and EGFR wild-type cells induced by RAD001, but could not reverse cell death in EGFR-sensitive mutant cells. Compared with EGFR wild-type/sensitive mutant cells, EGFR-resistant mutant cells were more sensitive to RAD001 combined with erastin. In addition, a high-dose of RAD001 reduced the expression levels of ferritin heavy-chain polypeptide 1 (FTH1), glutathione peroxidase 4 (GPX4) and ferroportin and significantly increased ROS and malondialdehyde (MDA) levels in EGFR-resistant mutant and EGFR wild-type cells. In the present study, GPX4 inhibitor only or combined with RAD001 inhibited the AKT/mTOR pathway in EGFR-resistant mutant cells. Therefore, the results of the present study suggested that inhibition of the mTOR pathway may downregulate the expression of ferroptosis-related proteins in EGFR-resistant and EGFR wild-type NSCLC cells, increase the ROS and MDA levels and ultimately induce ferroptosis.

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Chemoresistance Mechanisms in Non-Small Cell Lung Cancer—Opportunities for Drug Repurposing

Kaur,

Suresh

2023

Appl Biochem Biotechnol

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Chlorpromazine cooperatively induces apoptosis with tyrosine kinase inhibitors in EGFR-mutated lung cancer cell lines and restores the sensitivity to gefitinib in T790M-harboring resistant cells

Cited by 8 publications

References 36 publications

Investigation of nuclear DNA content and cell cycle phases in rat liver cells under chlorpromazine administration

Investigation of nuclear DNA content and cell cycle phases in rat liver cells under chlorpromazine administration

Mechanism of targeting the mTOR pathway to regulate ferroptosis in NSCLC with different EGFR mutations

Chemoresistance Mechanisms in Non-Small Cell Lung Cancer—Opportunities for Drug Repurposing

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