Gefitinib suppresses cervical cancer progression by inhibiting cell cycle progression and epithelial‑mesenchymal transition

Zheng, Jingbin; Yu, Jianxin; Yang, Min; Tang, Li

doi:10.3892/etm.2019.7754

Cited by 7 publications

(8 citation statements)

References 27 publications

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“…In addition to discovering novel drug candidates, this novel framework shows productive results when we evaluating the IC50 values of previously associated cervical cancer drug candidates. The host-targeted drugs afatinib ( 31 ), gefitinib ( 34 ), sirolimus ( 43 ), and temsirolimus ( 40 ) were found to be more effective than the FDA-approved drug for cervical cancer (i.e., topetecan) when their IC50 values were compared. Accordingly, these IC50 results have further strengthened our confidence in our observations and our developed system.…”

Section: Discussionmentioning

confidence: 99%

Drug repositioning via host-pathogen protein-protein interactions for the treatment of cervical cancer

2023

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IntroductionIntegrating interaction data with biological knowledge can be a critical approach for drug development or drug repurposing. In this context, host-pathogen-protein-protein interaction (HP-PPI) networks are useful instrument to uncover the phenomena underlying therapeutic effects in infectious diseases, including cervical cancer, which is almost exclusively due to human papillomavirus (HPV) infections. Cervical cancer is one of the second leading causes of death, and HPV16 and HPV18 are the most common subtypes worldwide. Given the limitations of traditionally used virus-directed drug therapies for infectious diseases and, at the same time, recent cancer statistics for cervical cancer cases, the need for innovative treatments becomes clear.MethodsAccordingly, in this study, we emphasize the potential of host proteins as drug targets and identify promising host protein candidates for cervical cancer by considering potential differences between HPV subtypes (i.e., HPV16 and HPV18) within a novel bioinformatics framework that we have developed. Subsequently, subtype-specific HP-PPI networks were constructed to obtain host proteins. Using this framework, we next selected biologically significant host proteins. Using these prominent host proteins, we performed drug repurposing analysis. Finally, by following our framework we identify the most promising host-oriented drug candidates for cervical cancer.ResultsAs a result of this framework, we discovered both previously associated and novel drug candidates, including interferon alfacon-1, pimecrolimus, and hyaluronan specifically for HPV16 and HPV18 subtypes, respectively.DiscussionConsequently, with this study, we have provided valuable data for further experimental and clinical efforts and presented a novel bioinformatics framework that can be applied to any infectious disease.

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Section: Discussionmentioning

confidence: 99%

Drug repositioning via host-pathogen protein-protein interactions for the treatment of cervical cancer

2023

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“…In addition to these clinical trials, several preclinical studies have investigated the mechanism of action of gefitinib in cervical cancer. EGFR overexpression has been identified in various types of cervical cancer, and preclinical studies have shown that inhibition of EGFR signalling can lead to decreased cell proliferation, migration, and invasion in cervical cancer cell lines [ 13 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…Gefitinib is a first-generation EGFR tyrosine kinase inhibitor (TKI) that is widely used in the treatment of lung cancer [ 14 , 15 ]. It acts by inhibiting the activity of the EGFR tyrosine kinase, which prevents downstream signalling pathways from being activated, inhibits cell cycle progression, inhibits epithelial–mesenchymal transition, and induces apoptosis in cervical cancer cells leading to inhibition of tumour cell growth and proliferation [ 12 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of EGFR inhibitor gefitinib in recurrent or metastatic cervical cancer: a preliminary report

Krishna,

Sathya,

Mukesh

et al. 2023

Med Oncol

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There has been growing interest in the use of epidermal growth factor receptor inhibitors in various cancers. The study was conducted to evaluate the efficacy and safety of gefitinib as a monotherapy in patients with recurrent or metastatic cervical cancer. Patients with cervical carcinoma who experienced locoregional recurrence or distant metastases either at presentation or after definitive combined chemoradiotherapy or postoperative radiotherapy were enrolled. Gefitinib was administered orally at a dose of 250 mg/d to eligible patients. Treatment with Gefitinib was continued until disease progression, intolerable adverse effects were developed, or consent was withdrawn. Clinical and radiological investigations were used to verify the disease response. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The study enrolled 32 patients who met the eligibility criteria. Thirty patients were available for the analysis. The majority of the patients included in the analysis had FIGO stage IIIB disease at their initial presentation. The median follow-up time was 6 months (3–15 months). Two patients (7%) had a complete clinical response, 7 patients (23%) had a partial response, 5 patients (17%) showed a stable disease and 16 patients had progressive disease (53%). The disease control rate was 47%. The median PFS was noted to be 4.5 months and the 1-year PFS was 20%. None of the individuals experienced toxicity of grade 3 or higher. All toxicities were managed conservatively. The study suggests that gefitinib may be a promising therapeutic option for patients with advanced cervical cancer who have limited treatment alternatives.

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“…EGFR-TKIs are known to retard cell cycle progression to elicit their anticancer effect. 13,14 HCC827 and H1975, representing gefitinib-sensitive and -resistant cells, respectively, were incubated with flunarizine (5 or 10 μM) alone or its combination with gefitinib (0.01/ 0.05 μM in HCC827 or 5/10 μM in H1975 cells) for 24 h. Consistent with literature-reported findings, gefitinib produced much less G1 arrest in H1975 (gefitinib-resistant) than in HCC827 (gefitinib-sensitive) cells (Figure 3). Thus, the less effective G1 cell cycle arrest following gefitinib treatment in our cell models is associated with resistance to the TKI.…”

Section: Clinically Approved Non-oncology Drugs Werementioning

confidence: 99%

Circumvention of Gefitinib Resistance by Repurposing Flunarizine via Histone Deacetylase Inhibition

To,

Chow,

Cheung

et al. 2023

ACS Pharmacol. Transl. Sci.

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Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) for treating advanced nonsmall cell lung cancer (NSCLC). However, drug resistance seriously impedes the clinical efficacy of gefitinib. This study investigated the repositioning of the non-oncology drug capable of inhibiting histone deacetylases (HDACs) to overcome gefitinib resistance. A few drug candidates were identified using the in silico repurposing tool "DRUGSURV" and tested for HDAC inhibition. Flunarizine, originally indicated for migraine prophylaxis and vertigo treatment, was selected for detailed investigation in NSCLC cell lines harboring a range of different gefitinib resistance mechanisms (EGFR T790M, KRAS G12S, MET amplification, or PTEN loss). The circumvention of gefitinib resistance by flunarizine was further demonstrated in an EGFR TKI (erlotinib)-refractory patient-derived tumor xenograft (PDX) model in vivo. The acetylation level of cellular histone protein was increased by flunarizine in a concentration-and time-dependent manner. Among the NSCLC cell lines evaluated, the extent of gefitinib resistance circumvention by flunarizine was found to be the most pronounced in EGFR T790Mbearing H1975 cells. The gefitinib−flunarizine combination was shown to induce the apoptotic protein Bim but reduce the antiapoptotic protein Bcl-2, which apparently circumvented gefitinib resistance. The induction of Bim by flunarizine was accompanied by an increase in the histone acetylation and E2F1 interaction with the BIM gene promoter. Flunarizine was also found to upregulate E-cadherin but downregulate the vimentin expression, which subsequently inhibited cancer cell migration and invasion. Importantly, flunarizine was also shown to significantly potentiate the tumor growth suppressive effect of gefitinib in EGFR TKIrefractory PDX in vivo. The findings advocate for the translational application of flunarizine to circumvent gefitinib resistance in the clinic.

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Gefitinib suppresses cervical cancer progression by inhibiting cell cycle progression and epithelial‑mesenchymal transition

Cited by 7 publications

References 27 publications

Drug repositioning via host-pathogen protein-protein interactions for the treatment of cervical cancer

Drug repositioning via host-pathogen protein-protein interactions for the treatment of cervical cancer

Efficacy and safety of EGFR inhibitor gefitinib in recurrent or metastatic cervical cancer: a preliminary report

Circumvention of Gefitinib Resistance by Repurposing Flunarizine via Histone Deacetylase Inhibition

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