Heme-Dependent ER Stress Apoptosis: A Mechanism for the Selective Toxicity of the Dihydroartemisinin, NSC735847, in Colorectal Cancer Cells

Abstract

Colorectal cancer (CRC) is a leading cause of cancer death in the United States. Artemisinin derivatives, including the dihydroartemisinin (DHA) monomers, are widely used as clinical agents for the treatment of malaria. Numerous studies demonstrate that these molecules also display antineoplastic activity with minimal toxicity. Of interest, dimeric DHA molecules are more active than their monomeric counterparts. Our previous data showed that the DHA dimer, NSC735847, was a potent inducer of death in different cancer cell types. However, the mechanism of action and activity of NSC735847 in colon cancer cells was not explored. The present study investigated the anticancer activity of NSC735847 and four structurally similar analog in human tumorigenic (HT-29 and HCT-116) and non-tumorigenic (FHC) colon cell lines. NSC735847 was more cytotoxic toward tumorigenic than non-tumorigenic colonocytes. In addition, NSC735847 exhibited greater cytotoxicity and tumor selectivity than the NSC735847 derivatives. To gain insight into mechanisms of NSC735847 activity, the requirement for endoplasmic reticulum (ER) stress and oxidative stress was tested. The data show that ER stress played a key role in the cytotoxicity of NSC735847 while oxidative stress had little impact on cell fate. In addition, it was observed that the cytotoxic activity of NSC735847 required the presence of heme, but not iron. The activity of NSC735847 was then compared to clinically utilized CRC therapeutics. NSC735847 was cytotoxic toward colon tumor cells at lower concentrations than oxaliplatin (OX). In addition, cell death was achieved at lower concentrations in colon cancer cells that were co-treated with folinic acid (Fol), 5-FU (F), and NSC735847 (FolFNSC), than Fol, F, and OX (FolFOX). The selective activity of NSC735847 and its ability to induce cytotoxicity at low concentrations suggest that NSC735847 may be an alternative for oxaliplatin in the FolFOX regimen for patients who are unable to tolerate its adverse effects.

Damage-associated molecular pattern (DAMP) activation in melanoma: investigation of the immunogenic activity of 15-deoxy, Δ12,14 prostamide J2

“…In different model systems, PERK was the predominant regulator of DAMP induction and cell death [ 9 , 11 ]. Therefore, to gain insight into mechanisms underlying 15dPMJ 2 -induced DAMP exposure, the ER stress pathway was probed utilizing the small-molecule PERK inhibitor, GSK2606414 [ 10 ]. 15dPMJ 2 -mediated cell surface expression of CRT was abrogated by GSK2606414 in B16F10 cells ( Figure 5A ).…”

“…To reestablish ER homeostasis, three sensors: PERK, IRE-1, and ATF6 are activated to promote cell survival. However, if the levels of ER stress are insurmountable, transcriptional activation of CHOP10 leads to the initiation of programmed cell death [ 10 ]. In numerous studies, DAMP inducing agents required the activity of PERK to initiate DAMP emission and cell death [ 9 , 11 ].…”

“…However, proliferation rates in non-cancerous cells are typically low and as a consequence, these cells have minimal protein folding loads and ER stress levels. Hence, ER stress inducing agents cause death preferentially in cancer cells because the death threshold is more readily reached [ 10 , 13 ]. This selective tumor targeting often results in reduced adverse effects, a desired property for chemotherapeutic agents.…”

Repositioning of Antiparasitic Drugs for Tumor Treatment

“…Many studies have indicated that ARTs increase the expression of cleaved caspase-3 and PARP in a variety of cancer cells by producing excessive amounts of ROS, thus inducing apoptosis in cancer cells ( 98 – 100 ). Further, excessive amounts of ROS may trigger an ER stress response in cancer cells ( 99 ), but the specific mechanism is not clear. Interestingly, increasing the concentration of ferrous ions and oxygen in the tumor environment to further increase the concentration of ROS has been shown to enhance the anticancer activity of ARTs ( 101 , 102 ), which provides a possible strategy for the development of new anticancer drugs based on ARTs.…”

Repurposing approved drugs for cancer therapy

“… 87 Artemisinin (malaria treatment) derivatives may be an alternative to oxaliplatin, as they are cytotoxic against colon cancer cells lines at low concentrations when used in combination with leucovorin and 5-fluorouracil (FOLNSC combination). 88 …”