An mTOR and DNA-PK dual inhibitor CC-115 hinders non-small cell lung cancer cell growth

Abstract

Molecularly-targeted agents are still urgently needed for better non-small cell lung cancer (NSCLC) therapy. CC-115 is a potent DNA-dependent protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR) dual blocker. We evaluated its activity in different human NSCLC cells. In various primary human NSCLC cells and A549 cells, CC-115 potently inhibited viability, cell proliferation, cell cycle progression, and hindered cell migration/invasion. Apoptosis was provoked in CC-115-stimulated NSCLC cells. The dual inhibitor, however, was unable to induce significant cytotoxic and pro-apoptotic activity in the lung epithelial cells. In primary NSCLC cells, CC-115 blocked activation of mTORC1/2 and DNA-PK. Yet, CC-115-induced primary NSCLC cell death was more potent than combined inhibition of DNA-PK plus mTOR. Further studies found that CC-115 provoked robust oxidative injury in primary NSCLC cells, which appeared independent of mTOR-DNA-PK dual blockage. In vivo studies showed that CC-115 oral administration in nude mice remarkably suppressed primary NSCLC cell xenograft growth. In CC-115-treated NSCLC xenograft tissues, mTOR-DNA-PK dual inhibition and oxidative injury were detected. Together, CC-115 potently inhibits NSCLC cell growth.

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“…CC-115, recognized as a dual inhibitor targeting mTOR kinase and DNA-dependent protein kinase, has demonstrated effectiveness in eliminating cancer cells with heightened oxidative stress levels, as evidenced in renal cell carcinoma, melanoma, and non-small cell lung cancer studies. [61][62][63][64][65] Furthermore, its well-tolerated nature in the initial phase I trial has been established. 62 Pyronaridine, an aminoquinoline-based antimalarial drug, 66 has shown potential in overcoming cancer treatment resistance but remains relatively unexplored in breast cancer.…”

Implication of mTOR Signaling in NSCLC: Mechanisms and Therapeutic Perspectives

“…There are also novel pharmacological agents with dual blocking action capable of modulating two different targets at once. For example, CC-115 represents a novel drug that can potently inhibit both mTORC1 and mTORC2, as well as DNA-dependent protein kinase (DNA-PK) and has demonstrated suppression of NSCLC growth both in vivo and in vitro [72]. Interestingly, research is also revealing new effects of mTOR inhibition on cancer cells which can be exploited for further therapeutic targeting [73].…”

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“…Briefly, an adequate number of cells were seeded using cover slides and cultured to maximally 90% confluence. Culture medium was exchanged, and half of the samples were treated with 5 µM of DNA-PK and mTor inhibitor CC-115 to ensure a sufficient blockage of DNA-PK according to previous findings [28,29]. After incubation of 24 h at 37 °C, cells were irradiated with a dose of 10 Gy by an ISOVOLT Titan X-ray generator (GE, Ahrensburg, Germany).…”