Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor

Abstract

While chemotherapy remains a mainstay in cancer treatment, growing evidence indicates that it may stimulate tumor growth. Other cancer therapies including radiation, immunotherapy, and stem cell transplantation may also trigger the release of pro‐inflammatory and pro‐tumorigenic cytokines in the tumor stroma. We recently demonstrated that although cancer therapy reduces tumor burden by killing tumor cells, the resulting dead cells, or ‘debris', can promote tumor growth by stimulating the release of cytokines. Chemotherapy fails to generate remission in over 70% of patients with ovarian cancer, is rarely curative, and simultaneously creates tumor cell debris. Thus, cancer therapy is inherently a double‐edged sword and targeting a single cytokine or pathway may not prevent therapy‐induced cancer. Soluble epoxide hydrolase (sEH) inhibitors have been shown to stimulate the resolution of inflammation by promoting the synthesis of pro‐resolving mediators and counter‐regulating pro‐inflammatory cytokines. In this study, tumor cell debris was prepared in vitro by treating either murine or human ovarian tumor cells with first‐line platinum or taxane‐based cytotoxic chemotherapies used for treating ovarian cancer (e.g. cisplatin, carboplatin, or paclitaxel). Chemotherapy‐generated tumor cell debris stimulated ovarian tumor growth in both immunocompetent and immunocompromised hosts. Debris triggered macrophage production of a series of pro‐inflammatory and pro‐angiogenic cytokines. Further, LC‐MS‐MS–based oxylipin profiling of tumor cell debris generated by chemotherapy revealed a pathological release of tumor‐promoting bioactive lipids (‘eicosanoid storm’) including cyclooxygenase (COX)‐derived prostaglandins, lipoxygenase‐derived HETEs, CYP450‐derived DiHOMEs and EpOMEs. We hypothesize that dual COX‐2/sEH inhibition may be a novel modality in suppressing ovarian tumor growth by stimulating the natural debris‐clearing process. A dual COX‐2/sEH inhibitor, PTUPB, suppressed debris‐induced cytokines (e.g. TNFα, CCL2, CCL4, CXCL2, G‐CSF, ICAM‐1, MMP‐9, and PAI‐1) and eicosanoids (e.g. PGF2a, PGD2, and PGJ2). PTUPB also delayed the onset of debris‐stimulated tumor growth in an ovarian cancer (ID8) model, achieving sustained survival over 80 days post‐injection. It is imperative to overcome the predicament between killing tumor cells and the inherent tumor‐promoting activity of the debris. Thus, dual inhibition of COX‐2/sEH may be a novel approach in cancer therapy to suppress the therapy‐induced cytokine/eicosanoid storm and debris‐stimulated tumor growth. Support or Funding Information National Cancer Institute grant RO1 01CA170549‐02; ROCA148633‐01A4; NIEHS Superfund Research Program RO1 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence

“…Our previous studies developed a novel COX‐2 and sEH dual inhibitor, PTUPB. It has been reported to potentiate the antitumor efficacy of cisplatin, reduce kidney injury, and suppress the chemotherapy‐induced cytokine/lipid mediator surge and ovarian cancer . Inhibition of COX‐2/sEH by PTUPB blocks and even reverses the adverse toxicities caused by NSAIDs .…”

Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases

“…Cancer treatment is a double-edged sword, as surgery (including biopsy), chemotherapy, or radiation can induce tumor-dormancy escape and subsequent metastatic outgrowth by impairing tumor-specific immunity through inflammation-mediated growth signals and loss of resolution of inflammation (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Even anesthetics can impair inflammation resolution (17).…”

Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19?

“…However, this storm is not a selflimiting, singular event. SARS-CoV-2 causes massive cell death and cellular debris that activates inflammasomes [2], which in turn trigger a macrophage-derived "eicosanoid storm", a surge of pro-inflammatory bioactive lipid mediators, such as prostaglandins and leukotrienes, that fuels local inflammation [3][4][5]. A paradigm shift in the inflammation field is that the resolution of inflammation is an active biochemical process [5], implying that hyper-inflammation may result from a deficit in resolution.…”

“…These mediators promote clearance of cellular debris and activate anti-inflammatory programs to inhibit several (2), which in turn produce high quantities of eicosanoids generating an "eicosanoid storm". These eicosanoids subsequently stimulate the production of pro-inflammatory cytokines (3) by immune cells such as macrophages, generating a robust "cytokine storm" that in turn promotes further leukocytosis and immune cell infiltrates (4). This robust inflammatory response to viral infection promotes hyaline membrane formation (5) and subsequent acute respiratory distress syndrome.…”

“…Both SPMs and sEHIs downregulate the transcription regulator NF-κB [5,11], the center of eicosanoid-induced cytokine storms, which promotes the induction of pro-inflammatory cytokines and prostaglandin synthesis via cyclooxygenase (COX). Combined pharmacological abrogation of COX-2 and sEH activity also prevents cytokine and eicosanoid storms via debris clearance mechanisms [4], offering another promising therapeutic intervention.…”