Chalcomoracin inhibits cell proliferation and increases sensitivity to radiotherapy in human non-small cell lung cancer cells via inducing endoplasmic reticulum stress-mediated paraptosis

Abstract

Chalcomoracin (CMR) is a kind of Diels–Alder adduct extracted from the mulberry leaves. Recent studies showed that CMR has a broad spectrum of anticancer activities and induces paraptosis in breast cancer and prostate cancer cells. In this study, we investigated the effects of CMR against human non-small cell lung cancer cells and the underlying mechanisms. We found that CMR dose-dependently inhibited the proliferation of human lung cancer H460, A549 and PC-9 cells. Furthermore, exposure to low and median doses of CMR induced paraptosis but not apoptosis, which was presented as the formation of extensive cytoplasmic vacuolation with increased expression of endoplasmic reticulum stress markers, Bip and Chop, as well as activation of MAPK pathway in the lung cancer cells. Knockdown of Bip with siRNA not only reduced the cell-killing effect of CMR, but also decreased the percentage of cytoplasmic vacuoles in H460 cells. Moreover, CMR also increased the sensitivity of lung cancer cells to radiotherapy through enhanced endoplasmic reticulum stress. In lung cancer H460 cell xenograft nude mice, combined treatment of CMR and radiation caused greatly enhanced tumor growth inhibition with upregulation of endoplasmic reticulum stress proteins and activation of pErk in xenograft tumor tissue. These data demonstrate that the anticancer activity and radiosensitization effect of CMR result from inducing paraptosis, suggesting that CMR could be considered as a potential anticancer agent and radiation sensitizer in the future cancer therapeutics.

Long non-coding RNA CASC2 enhances irradiation-induced endoplasmic reticulum stress in NSCLC cells through PERK signaling

“…Clinically, drugs that activate ER stress can be combined with radiotherapy to treat cancer. For example, dhalcomoracin has been shown to inhibit cell proliferation and increases sensitivity to radiotherapy in NSCLC by inducing ER stress (Zhang et al 2020b). Phenethyl isothiocyanate in combination with Gefitinib induces apoptosis in NSCLC cells through ER stress-mediated Mcl-1 degradation (Zhang et al 2020a).…”

Mulberry Diels–Alder-type adducts: isolation, structure, bioactivity, and synthesis

“…Han et al showed for the first time that chalcomoracin (5) treatment markedly promoted paraptosis along with extensive cytoplasmic vacuolation derived from the endoplasmic reticulum, rather than apoptosis, in PC-3 and MDA-MB-231cell lines [141]. Subsequently, Zhang et al demonstrated that chalcomoracin (5) could inhibit cell proliferation and increase sensitivity to radiotherapy in human non-small cell lung cancer cells also via endoplasmic reticulum stress-mediated paraptosis mechanism [142]. Takashi et al revealed that mulberrofuran G (31) could induce apoptotic cell death in HL-60 via both the cell death receptor pathway by stimulation of death receptor, and the mitochondrial pathway by Topo (162) were reported for the first times to possess HIF-1 inhibitory effect in the Hep3B cell-based assay [71].…”

Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy

“…However, radiation can also inhibit cell proliferation by disrupting the neoplastic cells physically through damage to the cell membrane and organelles, and thereby interfering with signal transduction (47)(48)(49). Damage to several organelles including the endoplasmic reticulum, ribosome, lysosome, and mitochondria have been implicated in the effects of RT-induced tumor cell death (50)(51)(52)(53)(54)(55)(56)(57)(58)(59).…”