Actinomycin D and Telmisartan Combination Targets Lung Cancer Stem Cells Through the Wnt/Beta Catenin Pathway

Abstract

The failure of lung cancer treatments has been attributed mostly to the development of drug resistance, however the underlying cellular and molecular mechanisms are poorly understood. Cancer initiating stem cells (CSCs), present in tumors in a small percentage, play critical roles in the development of drug resistance, metastasis, and cancer relapse. Hence, novel treatments targeting both bulk cancer cells and CSCs are under intense investigation. Herein, we report that lung cancer cells grown on a 3D fibrous scaffold form tumoroids that resemble in vivo tumors, expand CSCs, and provide a platform to identify anti-CSC drugs. The screening of an NCI library of FDA-approved drugs using tumoroid cultures led to identification of Actinomycin D (AD) as a top CSC inhibitor. Since CSCs are mostly resident in the tumor’s inner core, AD was combined with an angiotensin receptor antagonist, Telmisartan (TS), which is known to increase drug permeability in tumors and was shown to have anti-CSC activity. Our results showed that AD + TS administered intra-tumorally was significantly more effective than either drug alone in both syngeneic and xenograft mouse models. The results of mechanistic studies revealed that CSC expansion in tumoroids was associated with activation of β catenin signaling and that AD + TS treatment reduced active β catenin levels in tumors. Together, these results establish the utility of the tumoroid culture system to expand CSCs ex vivo for targeted drug screening, to identify promising novel treatments with both anti-CSC and anti-cancer effects, and to individualize treatments for metastatic drug resistant lung cancer patients.

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

“…This might be due to the Tel effect on lung cancer stem cell markers in H1975 and ROC-Res-H1975 cells. Recent reports have shown that Tel alone can decrease the expression of lung cancer stem cell markers such as Oct4 and Nanog (40). Telmisartan pre-treatment increased the uptake of FITC in 3D spheroids of lung cancer cells.…”

Emerging agents that target signaling pathways in cancer stem cells

“…The combination of docetaxel (DTX) and sulforaphane (SFN), pyrvinium pamoate (PP), and phosphor-sulindac (OXT-328) can inhibit CSC self-renewal ability, the EMT (epithelial-mesenchymal transition), and drug resistance by decreasing β-catenin expression in BCSCs [50][51][52]. Additionally, actinomycin D (AD) and telmisartan (TS) can also decrease the CSC number and activity and reduce CSC marker expression (such as SOX2, ALDH1, and NOS2) in lung cancer by inhibiting the Wnt-β/catenin signaling pathway [53].…”

ACPA decreases non-small cell lung cancer line growth through Akt/PI3K and JNK pathways in vitro

“…The total protein of A549 cells were harvested on following 24-hour incubation with ACPA (where maximum effect was observed) using RIPA buffer supplemented with phosphatase (cat#ab201113, Abcam) and protease (cat#78430, Thermo Scientific) inhibitors. Simple western assay was conducted following manufacturer's guideline; 0.8 mg/ml (n = 4) of protein sample was separated on 12-230 kDa Wes Separation Module (cat#SM-W004, Protein Simple) 41 . Nano-immunoassay was performed using primary anti-human antibodies for Akt (S473, S474, and S472) (cat#mab2055), JNK (T183/Y185 and T221/Y223) (cat#mab1387) and phospho-specific Akt (cat#mab887) and phospho-specific rabbit anti-human JNK (cat#-mab1205) (all from R&D Systems).…”