In a new study, researchers showed both in vivo and in vitro that a combination therapy of a chemotherapeutic drug and an IL-1R antagonist could be a beneficial treatment strategy for malignant mesothelioma (MM). The article, titled “Inflammasome Modulation by Chemotherapeutics in Malignant Mesothelioma,” was published in the journal PLOS ONE.
MM is a rare but deadly cancer whose incidence has grown in the last decades, mainly due to past exposure to asbestos, one of its main risk factors. Despite efforts to discover effective therapeutic strategies against the disease and extend a patient’s lifespan, malignant mesothelioma remains very resistant to treatments — namely, radiation and chemotherapy.
Several research teams have shown that inflammation plays an important role in MM development. The inflammasome is part of the inflammation apparatus and is composed of sensors called NOD-like receptors (NLRs), such as the NLRP3. The NLRP3 inflammasome, after assembly into an extracellular multiprotein structure complex, activates and amplifies inflammatory pathways in response to microbes and other dangerous signals through an increase in pro-inflammatory cytokines such as interleukin 1β (IL-1β) and IL-18. The role of the inflammasome in carcinogenesis is still undefined, since different studies report both pro-and anti-tumorigenic effects, usually dependent on the type of cancer under analysis. In MM tumor cells and tissues, the NLRP3 inflammasome was found to be attenuated.
In light of this information, researchers theorized that mesothelioma treatment with chemotherapeutic drugs could increase the inflammasome levels, leading to cell death; it could also increase the levels of IL-1β and other pro-inflammatory molecules, which could ultimately promote tumor growth. Co-treatment with an IL-1β blocker (antagonist), however, could inhibit this latter harmful effect.
To prove their theory, researchers used two human MM tumor cell lines (Hmeso and H2373) and two chemotherapeutic drugs (doxorubicin and cisplatin). In vitro results showed that both chemotherapeutic drugs activated the NLRP3 inflammasome in both cell lines, but only cisplatin caused a significant increase in NLRP3 levels in H2373 cells. Furthermore, both drugs induced an increase of pro-inflammatory cytokines in both MM cell lines. In vivo studies in specific mice models showed that the combination therapy of cisplatin and IL-1R (receptor of interleukins) antagonist (Anakinra) had better treatment outcomes in comparison to cisplatin alone or other treatment control groups, including a decrease in tumor size and number.
Researchers concluded, “(…) a combination of chemotherapeutic drugs and IL-1R antagonist could be a possible strategy for inhibiting MM tumor growth. Our report is a very small first step in this direction and detailed in vivo studies with various models, chemotherapeutic drugs and tools to antagonize IL-1β are required to confirm the findings of this study and are presently in process.”