The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells

Abstract

The anticancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells-Manuscript Draft-Manuscript Number: KAUP-2019-0426R3 Full Title: The anticancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma

“…Resveratrol [144], which in CCA acts inhibiting autophagy, and THC [183] induce an increase in Dh-Cer in cancer cells by inhibiting dihydroceramide desaturase (Des-1), which leads to ER-stress-mediated autophagy promotion. Similarly, ABTL0812 induces impairment of Des-1 activity, resulting in the accumulation of Dh-Cer and activation of UPR response, which, in combination with TRIB3-mediated AKT/mTOR axis inhibition, triggers cytotoxic autophagy in CCA cells [158,160]. Interestingly, Des1 expression was found to be upregulated in CCA cell lines compared with their nontumor counterparts NHC3 cells [158], correlating with previous reports [184] where Des1 was found overexpressed in CCA tissue compared with normal biliary tract tissue.…”

“…During recent years, four additional reports have been published using autophagy inducers in preclinical models of CCA. Decitabine (a cytosine analog, DNA demethylating agent [156]) and miR-124 (associated with STAT3 signaling) [29] induce an epigenomic induction of autophagy, while phenformin (diabetes therapeutic biguanide compound [157]) and ABTL0812 (hydroxylated variant of linoleic acid) [158] induce autophagy-mediated CCA cell death by activating LKB1-AMPK pathway and by inducing ER stress activation and AKT/mTOR pathway inhibition, respectively. Decitabine can potentially modulate the response of cancer cells to chemotherapy and radiotherapy [159] and induced apoptosis and autophagy-dependent caspase-independent CCA cell death in vitro, reducing tumor growth in vivo [156].…”

“…As a consequence, apoptosis and autophagy are increased, along with an increase in ATG7, ATG5 and Beclin1 levels, therefore acting on mTOR-mediated ULK1 complex activation during initiation of autophagy. The last published report precisely determined the mechanism of action of ABTL0812, which induces cytotoxic autophagy on CCA cells by inducing robust and sustained ER stress [158,160], along with TRIB3-mediated Akt/mTOR axis inhibition [161]. Similar to dihydroartemisinin, at ABTL0812 concentrations that result in lethality for CCA cells in vitro, immortalized cholangiocytes remain alive, suggesting that this type of anti-cancer treatments may offer a safe approach.…”

“…Additionally, other types of cell stresses promote autophagy through the UPR (Unfolded Protein Response) and mediated by PERK, IRE1α or CAMKK2 protein [163]. PERK activation directly activates the ATG12-ATG5-ATG16L complex, which induces PERK-ATF4-CHOP pathway activation and TRIB3 (Tribbles homolog 3) expression, a pseudokinase that acts as an endogenous negative regulator of the AKT/mTOR axis [158,164,165]. IRE1α promotes Beclin1 liberation from Bcl2 and PI3K-Beclin1 complex activation [163].…”

“…ABTL0812 is the autophagy inductor currently being evaluated in CCA models with the most complete description of its mechanism of action, and it already showed preliminary clinical efficacy on a CCA patient derived from a phase I trial in patients with solid tumors [160,168]. In xenograft models, ABTL0812 potentiated gemcitabine plus cisplatin anticancer efficacy by upregulating TRIB3 and CHOP levels, two markers that have been validated for the first time as surrogate pharmacodynamic biomarkers in endometrial and lung cancer patients [158,160,169,170]. This novel strategy to induce ER-stress-mediated cytotoxic autophagy relies on the fact that cancer cells have evolved to use the UPR to survive the ER stress induced by the hostile conditions of tumor microenvironment (hypoxia, low glucose, intracellular acidification, etc.…”