Opaganib Protects against Radiation Toxicity: Implications for Homeland Security and Antitumor Radiotherapy

Abstract

Exposure to ionizing radiation (IR) is a lingering threat from accidental or terroristic nuclear events, but is also widely used in cancer therapy. In both cases, host inflammatory responses to IR damage normal tissue causing morbidity and possibly mortality to the victim/patient. Opaganib, a first-in-class inhibitor of sphingolipid metabolism, has broad anti-inflammatory and anticancer activity. Opaganib elevates ceramide and reduces sphingosine 1-phosphate (S1P) in cells, conditions that increase the antitumor efficacy of radiation while concomitantly suppressing inflammatory damage to normal tissue. Therefore, opaganib may suppress toxicity from unintended IR exposure and improve patient response to chemoradiation. To test these hypotheses, we first examined the effects of opaganib on the toxicity and antitumor activity of radiation in mice exposed to total body irradiation (TBI) or IR with partial bone marrow shielding. Oral treatment with opaganib 2 h before TBI shifted the LD75 from 9.5 Gy to 11.5 Gy, and provided substantial protection against gastrointestinal damage associated with suppression of radiation-induced elevations of S1P and TNFα in the small intestines. In the partially shielded model, opaganib provided dose-dependent survival advantages when administered 4 h before or 24 h after radiation exposure, and was particularly effective when given both prior to and following radiation. Relevant to cancer radiotherapy, opaganib decreased the sensitivity of IEC6 (non-transformed mouse intestinal epithelial) cells to radiation, while sensitizing PAN02 cells to in vitro radiation. Next, the in vivo effects of opaganib in combination with radiation were examined in a syngeneic tumor model consisting of C57BL/6 mice bearing xenografts of PAN02 pancreatic cancer cells and a cross-species xenograft model consisting of nude mice bearing xenografts of human FaDu cells. Mice were treated with opaganib and/or IR (plus cisplatin in the case of FaDu tumors). In both tumor models, the optimal suppression of tumor growth was attained by the combination of opaganib with IR (± cisplatin). Overall, opaganib substantially protects normal tissue from radiation damage that may occur through unintended exposure or cancer radiotherapy.

The Sphingolipid-Modulating Drug Opaganib Protects against Radiation-Induced Lung Inflammation and Fibrosis: Potential Uses as a Medical Countermeasure and in Cancer Radiotherapy

“…Efficacy of early treatment with opaganib. We previously reported that ad tion of opaganib to mice exposed to high-dose TBI with 5% bone marrow shiel tected the animals against GI-ARS and markedly improved 30-day survival [34] experiments, opaganib treatment was not started until 24 h after radiation exp model use of the drug as a medical countermeasure (MCM) to mitigate GI-ARS intentional, e.g., accidental or terroristic, radiation exposure. We therefore con similar short-term, post-radiation exposure experiment to determine if the opaga ment regimen that was active against GI-ARS improved the longer-term surviva Therefore, male C57BL/6 mice were exposed to 16 Gy TBI with 5% bone marrow and then treated with 0 or 150 mg/kg opaganib twice-daily (BID) for 5 days, beg h after irradiation (Groups B and C, respectively).…”

“…Efficacy of early treatment with opaganib. We previously reported that administration of opaganib to mice exposed to high-dose TBI with 5% bone marrow shielding protected the animals against GI-ARS and markedly improved 30-day survival [34]. In those experiments, opaganib treatment was not started until 24 h after radiation exposure to model use of the drug as a medical countermeasure (MCM) to mitigate GI-ARS from unintentional, e.g., accidental or terroristic, radiation exposure.…”

“…We have previously demonstrated that opaganib suppresses gastrointestinal acute radiation syndrome (GI-ARS) in mice after total body irradiation (TBI) with partial body shielding [34]. In the present study, we investigated the therapeutic activity of opaganib in models of lung inflammation induced by exposure to ionizing radiation.…”

“…Opaganib has antitumor activity in a wide range of mouse models (reviewed in [5]), and has shown promise in oncology [27,28] and COVID-19 [15,29] clinical trials. Additionally, opaganib has in vivo anti-inflammatory activity in several rodent models, including: ulcerative colitis, Crohn's disease, colitis-driven colon cancer, vascular permeability, rheumatoid arthritis, osteoarthritis, liver transplantation, hepatic ischemia-reperfusion injury, and acute kidney injury (Reviewed in [15], as well as bacterial pneumonia [30], lupus nephritis [31], psoriasis [32], renal fibrosis [33], and gastrointestinal acute radiation syndrome [34]. In models of inflammatory bowel disease, opaganib decreased levels of TNFα, IL-1β, IFN-γ, IL-6, and S1P levels in colon tissue [35].…”

Sphingolipid-Induced Bone Regulation and Its Emerging Role in Dysfunction Due to Disease and Infection

“…Further, Bonnaud et al [ 231 ] demonstrated that S1P protected human microvascular endothelial cells from ceramide-induced apoptosis following 15 Gy of IR, but not from DNA damage-induced mitotic death. Most notably, opaganib, a first-in-class inhibitor of sphingolipid metabolism via SPHK2, has been shown to deliver broad anti-inflammatory (via the downregulation of NF-κB and TNFα) and anti-cancer activity [ 232 ]. As such, opaganib acts as a sphingosine mimetic molecule and also inhibits DES1, thereby increasing levels of dihydroceramides and promoting autophagy [ 233 ].…”