The imidazoacridinone C-1311 induces p53-dependent senescence or p53-independent apoptosis and sensitizes cancer cells to radiation

Abstract

C-1311 is a small molecule, which has shown promise in a number of pre-clinical and clinical studies. However, the biological response to C-1311 exposure is complicated and has been reported to involve a number of cell fates. Here, we investigated the molecular signaling which determines the response to C-1311 in both cancer and non-cancer cell lines. For the first time we demonstrate that the tumor suppressor, p53 plays a key role in cell fate determination after C-1311 treatment. In the presence of wild-type p53, cells exposed to C-1311 entered senescence. In contrast, cells lines without functional p53 underwent mitotic catastrophe and apoptosis. C-1311 also induced autophagy in a non-p53-dependent manner. Cells in hypoxic conditions also responded to C-1311 in a p53-dependent manner, suggesting that our observations are physiologically relevant. Most importantly, we show that C-1311 can be effectively combined with radiation to improve the radiosensitivity of a panel of cancer cell lines. Together, our data suggest that C-1311 warrants further clinical testing in combination with radiotherapy for the treatment of solid tumors.

Anticancer Imidazoacridinone C-1311 is Effective in Androgen-Dependent and Androgen-Independent Prostate Cancer Cells

“…In contrast, AR-negative cells with mutated p53 underwent arrest in the G2/M phase of the cell cycle. These results are in agreement with our previous observations showing that C-1311 has the potential to kill cancer cells with an unfavorable p53 profile [16]. Strategies combining the standard anti-PCa therapy with cell cycle inhibitors targeting the G1 (palbociclib, ribociclib, AZD-5363, ipatasertib) or G2 (adavosertib) phases of the cell cycle are currently tested in several clinical trials in castration-resistant prostate cancer [48].…”

“…Next, we assessed the effect of C-1311 on the biological response of the PCa cells. C-1311, as a topoisomerase II inhibitor, has been previously demonstrated to induce DNA damage [ 16 ]. Correspondingly, we found that C-1311 treatment in LNCaP, 22Rv1, and DU-145 cells increased the phosphorylation of the histone H2AX (γH2AX) ( Figure 5 A), a well-known marker of DNA damage [ 40 ].…”

“…C-1311 is a DNA-damaging intercalator and inhibitor of topoisomerase II activity [13], which also blocks angiogenesis by targeting hypoxia-inducible factor 1α (HIF-1α) [14]. Additionally, C-1311 inhibits the oncogenic receptor tyrosine kinase FLT3 [15], and sensitizes p53-mutated cancer cells to radiation [16]. However, its efficacy in PCa cells never has been determined.…”

Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism

“…These data demonstrate that, although both VX-970 and VE-821 lead to an accumulation of p62, only VX-970 also impacts LC3. Next, OE21 cells were exposed to VX-970 in hypoxic conditions of <0.1% oxygen, which has been shown to induce autophagy ( Rzymski et al., 2010 ; Skwarska et al., 2017 ). As expected, exposure to hypoxia led to increased LC3-II and a decrease in p62.…”

Role of p53 in Regulating Radiation Responses

“…Allosteric inhibitors of the CXCR4 receptor block metastasis-associated cell activity stimulated by secretions from irradiated lung epithelial cells and may be effective as cancer therapy when combined with radiation therapy [ 179 ]. Treatment for cancer cells with imidazoacridinone C-1311 (SymadexTM) prior to irradiation causes senescence in the presence of p53 and apoptosis without p53 [ 180 ]. A combination of radiotherapy and drug therapy is also important.…”