Hypochlorous acid selectively promotes toxicity and the expression of danger signals in human abdominal cancer cells

Abstract

Tumors of the abdominal cavity, such as colorectal, pancreatic and ovarian cancer, frequently metastasize into the peritoneum. Large numbers of metastatic nodules hinder curative surgical resection, necessitating lavage with hyperthermic intraperitoneal chemotherapy (HIPEC). However, HIPEC not only causes severe side effects but also has limited therapeutic efficacy in various instances. At the same time, the age of immunotherapies such as biological agents, checkpoint-inhibitors or immune-cell therapies, increasingly emphasizes the critical role of anticancer immunity in targeting malignancies. The present study investigated the ability of three types of long-lived reactive species (oxidants) to inactivate cancer cells and potentially complement current HIPEC regimens, as well as to increase tumor cell expression of danger signals that stimulate innate immunity. The human abdominal cancer cell lines HT-29, Panc-01 and SK-OV-3 were exposed to different concentrations of hydrogen peroxide (H 2 O 2), hypochlorous acid (HOCl) and peroxynitrite (ONOO-). Metabolic activity was measured, as well as determination of cell death and danger signal expression levels via flow cytometry and detection of intracellular oxidation via high-content microscopy. Oxidation of tumor decreased intracellular levels of the antioxidant glutathione and induced oxidation in mitochondria, accompanied by a decrease in metabolic activity and an increase in regulated cell death. At similar concentrations, HOCl showed the most potent effects. Non-malignant HaCaT keratinocytes were less affected, suggesting the approach to be selective to some extent. Pro-immunogenic danger molecules were investigated by assessing the expression levels of calreticulin (CRT), and heat-shock protein (HSP)70 and HSP90. CRT expression was greatest following HOCl and ONOOtreatment, whereas HOCl and H 2 O 2 resulted in the greatest increase in HSP70 and HSP90 expression levels. These results suggested that HOCl may be a promising agent to complement current HIPEC regimens targeting peritoneal carcinomatosis.

Topical hypochlorous acid (HOCl) blocks inflammatory gene expression and tumorigenic progression in UV-exposed SKH-1 high risk mouse skin

“…HOCl adduction of relevant molecular targets remains poorly understood, and apart from modulation of inflammatory pathways HOCl has also been shown to display cancer cell-directed activities including GRP78-mediated modulation of ER stress, autophagy, and proteotoxicity. Specifically, GRP78-directed Lys353 oxidation and other molecular pathways have been involved in HOCl-associated antitumorigenic activity, a topic to be explored by future experiments in the context of HOCl-suppression of photocarcinogenesis [ 9 , 66 , 67 ]. Additionally, upregulation of the tumor suppressor gene Txnip observed by us in response to HOCl-exposure in the context of our UV-induced SKH-1 high risk mouse model might also be involved in the anti-tumorigenic activity of topical HOCl ( Fig.…”

Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer

“…In addition, HOCl-hydrogel formulations have shown immunotherapeutic efficacy against experimental murine melanoma (176). Consistent with these observations, a suppressive role of HOCl in the control of cancer cell viability and tumor progression has been envisioned and further substantiated (71,177,178).…”

BSA‐AIE Nanoparticles with Boosted ROS Generation for Immunogenic Cell Death Immunotherapy of Multiple Myeloma

“…[ 30 ] In addition, it was also reported that DAMP emission could be different for the same cancer cell lines depending on in vitro or in vivo treatment. [ 31 ] To evaluate the ICD induction and anti‐tumor immune response of our BSA/TPA‐Erdn nanoparticles in vivo, an NSG mice model without the immune system (T\B\NK cells) was built. Such an NSG mice model provides the opportunity to evaluate MM patients’ immune responses induced by our BSA/TPA‐Erdn, and its antitumor performance on human MM cell lines.…”