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. 2021 Sep;41(9):4215-4228.
doi: 10.21873/anticanres.15226. Epub 2021 Sep 1.

Telmisartan Facilitates the Anticancer Effects of CARP-1 Functional Mimetic and Sorafenib in Rociletinib Resistant Non-small Cell Lung Cancer

Sunil Kumar Surapaneni  1 , Ebony Nottingham  1 , Arindam Mondal  2 , Nilkumar Patel  1 , Peggy Arthur  1 , Aragaw Gebeyehu  1 , Anil Kumar Kalvala  1 , Arun K Rishi  3 , Mandip Singh  4
Affiliations

Telmisartan Facilitates the Anticancer Effects of CARP-1 Functional Mimetic and Sorafenib in Rociletinib Resistant Non-small Cell Lung Cancer

Sunil Kumar Surapaneni et al. Anticancer Res. 2021 Sep.

Abstract

Background/aim: Tyrosine kinase inhibitors (TKIs) are used for the treatment of both wild type and mutant non-small cell lung cancer (NSCLC); however, acquired resistance is a major clinical challenge. Herein, we aimed to investigate the effects of telmisartan (Tel), CFM 4.16 and sorafenib combination in rociletinib resistant NSCLC tumors.

Materials and methods: 3D spheroid cultures and western blotting were used for evaluating cytotoxic effects and protein expression. An in vivo rociletinib resistant H1975 xenograft model of NSCLC was developed by subcutaneous injection of rociletinib resistant H1975 cells into nude mice.

Results: Tel, CFM 4.16 and sorafenib combination displayed superior anti-cancer effects in 3D spheroid cultures and a rociletinib resistant H1975 xenograft model of NSCLC by decreasing the protein expression of oncogenic and cancer stem cell markers (Nanog, Sox2 and Oct4).

Conclusion: Tel facilitates effective penetration of CFM 4.16 and sorafenib in rociletinib resistant H1975 models of NSCLC.

Keywords: CFM 4.16; Non-small cell lung cancer; resistance.; rociletinib; sorafenib; telmisartan.

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Conflict of interest statement

Conflicts of Interest

The Authors declare that they have no conflicts of interest associated with this study.

Figures

Figure 1.
Figure 1.
Western blots and densitometric analysis of p-MET, MET, p-EGFR and EGFR in H1975 and rociletinib resistant H1975 cells. Data are representative of three different experiments and were presented as mean, and error bars refer to SEM. *p<0.05, **p<0.01, ***p<0.001 was considered significant when compared to control. MET: MET proto-oncogene, receptor tyrosine kinase; EGFR: epidermal growth factor receptor; Roc-Res-H1975: rociletinib resistant H1975.
Figure 2.
Figure 2.
Western blots and densitometric analysis of Nanog, Oct4 and Sox2 in H1975 and Rociletinib resistant H1975 cells. Data are representative of three different experiments and were presented as mean, and error bars refer to SEM. *p<0.05, **p<0.01, ***p<0.001 was considered significant when compared to control.
Figure 3.
Figure 3.
Flow cytometry analysis of uptake of FITC in control (untreated) and Tel pre-treated 3D spheroids. Data shown are representative of three independent experiments and presented as mean, and error bars refer to SEM. FITC: Fluorescein isothiocyanate.
Figure 4.
Figure 4.
Tel oral administration followed by CFM 4.16 NLF and sorafenib combination significantly inhibited the tumor growth in the rociletinib resistant H1975 xenograft model. Data represent mean±S.E.M. of 4 mice per group. ***p<0.001 and *p<0.05 significant vs. control.
Figure 5.
Figure 5.
Western blots and densitometric analysis of p-EGFR and p-MET in rociletinib resistant H1975 xenograft model of lung cancer. Data are representative of three different experiments and presented as mean, and error bars refer to SEM. ***p<0.001 was considered significant when compared to control. MET: MET proto-oncogene, receptor tyrosine kinase; EGFR: epidermal growth factor receptor.
Figure 6.
Figure 6.
Western blots and densitometric analysis of TGF-β, E-cadherin, MMP9, Nanog and Sox2 in rociletinib resistant H1975 xenograft model of lung cancer. Data are representative of three different experiments and presented as mean, and error bars refer to SEM. *p<0.05, **p<0.01, ***p<0.001 was considered significant when compared to control. TGF-: Transforming growth factor β; MMP9: matrix metalloproteinase 9.
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