Cantharidins Induce ER Stress and a Terminal Unfolded Protein Response in OSCC

Abstract

Mortality and morbidity associated with oral squamous cell carcinoma (OSCC) remain unacceptably high with disfiguring treatment options and a death rate of 1 per hour in the United States. The approval of cituximab for advanced OSCC has been the only new treatment for these patients since the 1970s, although it has not significantly increased overall survival. To address the paucity of effective new therapies, we undertook a high-throughput screen to discover small molecules and natural products that could induce endoplasmic reticulum (ER) stress and enforce a terminal unfolded protein response (UPR) in OSCC. The terpenoid cantharidin (CNT), previously used to treat various malignancies in culture-specific medical practices for over 2,000 y, emerged as a hit. CNT and its analog, cantharidic acid, potently induced protein and gene expression profiles consistent with the activation of ER stress, the UPR, and apoptosis in OSCC cells. Murine embryonic fibroblasts null for the UPR-associated transcription factors Atf4 or Chop were significantly protected from CNT, implicating a key role for the UPR in the death response. These data validate that our high-throughput screen can identify novel modulators of UPR signaling and that such compounds might provide a new therapeutic approach to treating patients with OSCC.

Cantharidic acid induces apoptosis of human leukemic HL‐60 cells via c‐Jun N‐terminal kinase‐regulated caspase‐8/‐9/‐3 activation pathway

“…The present study was undertaken to investigate the antileukemic effect of another lipophilic structural analogue of CTD, CAC, and its underlying mechanisms. Xi et al recently indicated that CAC showed more potent antiproliferative effect than CTD and NCTD in oral squamous cell carcinoma cells . Herein, we demonstrated that CAC also possesses an antileukemic effect on AML cells, and its anticancer activity was attributed to its induction of G2/M cell‐cycle arrest and apoptosis.…”

“…Until now, most research focused on investigating the anticancer effects of CTD and NCTD, however, the tumor suppressive effects of another CTD lipophilic structural analogue, cantharidic acid (CAC), have not been clearly defined. CAC was reported to inhibit growth of oral squamous cell carcinoma (OSCC) and testicular germ cell tumor respectively through endoplasmic reticulum (ER) stress and unfolded protein response (UPR) induction and ERK‐mediated caspase‐3 activation . Moreover, Feng et al reports that CAC induces apoptosis in SK‐Hep‐1 cells through a p38‐mediated apoptotic pathway …”

Cantharidin‐induced LO2 cell autophagy and apoptosis via endoplasmic reticulum stress pathway in vitro

“…Modern studies have found that many drugs can induce hepatotoxicity through ERS such as paracetamol and anti‐type 2 diabetes drugs (ciglitazone and troglitazone), and some TCMs including Polygonum multiflorum , Matrine, psoralea, and Coptis chinensis have been reported to induce hepatotoxicity in association with ERS (Liu, Li, & Zhang, 2019). Furthermore, ERS can mediate autophagy and apoptosis based on unfolded protein response (UPR), calcium signaling, and tumor protein p53 (P53) signaling, and accumulation of unfolded or misfolded proteins in the ER leads to UPR, which are important in cellular self‐defense (Li et al, 2010; Qiu et al, 2019; Tian, Zeng, Li, Wu, & Wang, 2015; Wang, Chow, Chien, & Lin, 2018; Xi et al, 2015). These two processes have also been reported to play an important role in drug‐induced hepatotoxicity (Yongke & Arthur, 2015; Zhang et al, 2019).…”

Cantharidic acid induces apoptosis through the p38 MAPK signaling pathway in human hepatocellular carcinoma

“…Our previous study also showed that, compared with the IC50 (21 μM) of cantharidin, anhydride‐modified cantharidin analogs exhibited low cytotoxicity (IC50 > 200 μM) in primary cultured rat hepatocytes . CA is a hydrolysis product of cantharidin and is a cantharidin analog; it exhibits more hydrophilic ability and bioavailability than other cantharidin analogs . However, the exact effect of CA on HCC is still unknown.…”

“…15 CA is a hydrolysis product of cantharidin and is a cantharidin analog; it exhibits more hydrophilic ability and bioavailability than other cantharidin analogs. 11 However, the exact effect of CA on HCC is still unknown. Recent studies demonstrate that inhibition of protein phosphatase 2A (PP2A) activity has been linked to mitogenactivated protein kinase (MAPK) activation and caspase-3 cleavageassociated apoptosis.…”