Pemetrexed (PEM) is a useful drug that can be combined with immune checkpoint blockade therapy for treatment of patients with advanced non–small‐cell lung cancer (NSCLC). However, its effects on anti–cancer immunity, especially the sensitivity of NSCLC cells to cytotoxic immune cells, have not been fully investigated. In this study, we examined the effects of PEM on the sensitivity of human NSCLC cells to two different types of cytotoxic immune cells. Pre‐treatment with PEM increased the sensitivity of two NSCLC cell lines, PC9 and A549, to activated T cells and natural killer (NK) cells, and decreased the expression of anti–apoptotic proteins, including XIAP and Mcl‐1. In addition, PEM treatment increased the cell surface expression of programmed death‐ligand 1 (PD‐L1) on PC9 cells. PEM‐induced upregulation of PD‐L1 on PC9 cells was at least partially ascribed to activation of ERK and the NFκB pathway. In contrast, PEM treatment increased the expression of UL16‐binding proteins (ULBP), ligands for the NKG2D NK receptor, on PC9 and A549 cells, as well as the induction of senescence. Although the addition of anti–programmed cell death 1 antibody showed no effect on the sensitivity of PEM‐treated PC9 and A549 cells to activated T cells, that of anti–NKG2D antibody decreased the enhanced sensitivity of PEM‐treated A549 cells to NK cells. These results indicate that PEM can effectively sensitize human NSCLC cells to cytotoxic immune cells while modulating the expression of immune‐regulatory molecules.
Inhibition of CDK4/6 slows the cell cycle and induces senescence in breast cancer cells. However, senescent cancer cells promote invasion and metastasis. Several drugs reportedly target senescent cells, including . We examined the effects of the CDK4/6 inhibitor abemaciclib and ABT-263 on two human breast cancer cell lines. The abemaciclib and ABT-263 combination additively decreased the viability of MDA-MB-231 cells, but not MCF-7 cells. Also, the combination therapy-induced caspase-dependent apoptosis in MDA-MB-231 cells. Combination therapy with abemaciclib and ABT-737, an ABT-263 analog, significantly suppressed the in vivo growth of MDA-MB-231 with transient bodyweight loss. Given that p16 Ink4a and p21 Cip1/Waf1 are key factors in senescence and that both cell lines were negative for p16, the role of p21 in apoptosis of treated breast cancer cells was investigated. Although abemaciclib increased the cytoplasmic p21 level in both cell lines as a hallmark of senescence, the abemaciclib and ABT-263 combination decreased it only in MDA-MB-231 cells. This decrease of p21 expression was relieved by caspase inhibition, and p21 was colocalized with caspase-3 in the cytoplasm of MDA-MB-231 cells. Alternatively, small interfering RNA-mediated knockdown of p21 rendered caspase-3-negative MCF-7 cells susceptible to abemaciclib and ABT-263, as well as TNF-related apoptosisinducing ligand. Furthermore, a clinical database analysis showed that p21 high breast cancer patients had a poorer prognosis compared to p21 low patients. These results suggest that cytoplasmic p21 plays a protective role in apoptosis of CDK4/6 inhibitor-induced senescent breast cancer cells.
The interim and final results of randomized controlled trials on the efficacy of lung cancer computed tomography (CT) screening have been reported recently from Western countries. The outcome of the National Lung Screening Trial (NLST) demonstrated the efficacy of low-dose thoracic CT screening for heavy smokers; however, other studies have found no apparent reduction in the mortality rate, and the outcome of the NELSON study is awaited. To date, a few studies have reported on the efficacy of lung cancer CT screening for non-/light smokers. A report from the Hitachi district, which is an ecological/time series study where non-/light smokers account for approximately half of the CT screening examinees, was published in 2012, with an outcome suggesting efficacy. Currently, a randomized controlled trial (JECS Study) is underway in Japan with non-/light smokers as the subjects, and this trial is very important in terms of cancer prevention.
Objective Therapy‐induced senescent cancer cells increase the expression of the cyclin‐dependent kinase inhibitors p16Ink4a and p21Cip1/Waf1. Given that p21 regulates not only the cell cycle but also cell death, we investigated the roles of p21 in cell death using a p16‐negative A549 human lung adenocarcinoma cell line. Methods Senescence was induced by doxorubicin (DXR) or pemetrexed (PEM). The protein expression of p21 was examined by immunoblot. Cell death, reactive oxygen species (ROS) and lipid peroxidation were determined by flow cytometry. ABT‐263 and ABT‐737 were used as senolytic drugs. In vivo growth of A549 cells with different levels of p21 and their sensitivity to PEM were examined in xenograft models. Results DXR‐induced senescent A549 cells increased the expression of cytoplasmic p21, and the sensitivity to ABT‐263 was augmented in p21‐knockout A549 (A549‐KOp21) cells. A similar senolytic effect was observed when PEM was combined with ABT‐737. PEM alone induced a higher level of non‐apoptotic cell death, ferroptosis, in A549‐KOp21 cells than in A549 cells. Although there was no difference in the level of lipid peroxidation, ROS levels were higher in PEM‐treated A549‐KOp21 cells than in PEM‐treated A549 cells. A loss of p21 increased the sensitivity of A549 cells to PEM both in vitro and in vivo. A clinical database analysis showed that CDKN1Ahigh lung adenocarcinoma patients had a poorer prognosis compared to CDKN1Alow patients. Conclusion Cytoplasmic p21, which was increased in therapy‐induced senescent lung cancer cells, plays protective roles in senolysis and ferroptosis.
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