Inflammasome inhibitors: promising therapeutic approaches against cancer

In the past, thalidomide has mainly been used as a sedative or hypnotic drug to treat anxiety, insomnia, gastritis, and tension [79]. The antitumor activity of thalidomide was discovered when it was used for the treatment of erythema nodosum leprosum because of its antiangiogenic properties [80]. However, due to its potential to cause congenital defects, thalidomide analogs have mostly been applied to many types of cancer, including prostate cancer and multiple myeloma.

For the treatment of multiple myeloma, thalidomide has been approved for first-line therapy in combination with other chemotherapeutic drugs [81]. In patients with relapsed myeloma, few therapies are available. However, researchers have found that thalidomide has a practical antitumor effect on patients with advanced myeloma. According to statistics, 10% of patients experience complete or almost complete remission and 32% exhibit a decrease in serum or urine paraprotein levels. In most patients, the percentage of plasma cells in the bone marrow is reduced, and the hemoglobin level is elevated, indicating substantial antitumor activity against myeloma [55]. In a randomized phase II trial, the combination of thalidomide and docetaxel resulted in a significant reduction in the prostate-specific antigen level and an elevation of the median survival rate in patients with metastatic androgen-independent prostate cancer [54]. The mechanism of malignancy control with thalidomide might involve its antiangiogenic activity. Thalidomide was demonstrated to reduce the high levels of certain angiogenic factors, such as fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) [82]. Moreover, thalidomide enhances cell-mediated immunity by directly interacting with cytotoxic T cells, which are lethal to tumor cells [83].

However, the application of thalidomide in other carcinomas has not shown significant efficacy. In unresectable hepatocellular carcinoma, thalidomide is tolerated in most patients with gradual dose escalation, but its monotherapeutic activity is modest compared with that of the combined therapy [84]. In a randomized, double-blinded, placebo-controlled trial, 722 patients with advanced non-small cell lung cancer were treated with thalidomide in combination with gemcitabine and carboplatin. The results showed that this treatment regimen did not improve the survival rate but did increase the risk of thrombotic events [85]. Moreover, this outcome was also demonstrated in a phase III clinical trial performed in France, and neuropathy was the most common adverse event observed [86]. Additionally, in patients with metastatic melanoma, the combination of thalidomide and dacarbazine or temozolomide shows limited efficacy. Constipation, peripheral neuropathy, fatigue, edema, and rash are attributed to thalidomide [87, 88].

Overall, thalidomide is widely used in the treatment of multiple myeloma and prostate cancer. Especially in multiple myeloma, the combination of melphalan-prednisone-thalidomide is deemed a standard therapy for patients ineligible for stem cell transplantation [89]. However, its antitumor activity has a moderate effect on other types of cancer.

Anakinra is a recombinant form of interleukin-1 receptor antagonist (IL-1Ra), which is commonly applied in the treatment of rheumatoid arthritis and autoinflammatory disease [90].

Previous studies with myeloma cells have shown that anakinra can significantly reduce IL-6 levels but does not increase myeloma cell death. However, a combination therapy of anakinra and dexamethasone induces cell death in myeloma cells [91]. In a study of breast cancer mouse models, anakinra decreased the growth of tumors in the bone and reduced the number of mice with bone metastasis from 90% (placebo) to 40% (treatment) or 10% (preventative). This study indicated that anakinra fails to increase tumor cell death but represses cell proliferation and angiogenesis [57]. Melanoma, the most dangerous type of skin cancer, has a poor prognosis. A study found that anakinra increases M1 macrophage polarization and decreases myeloid-derived suppressor cell numbers in mice with melanoma [56]. In phase II clinical trials, researchers investigated the roles of anakinra and low-dose dexamethasone in patients with smoldering or indolent multiple myeloma. The results showed that anakinra targets the progressed myeloma fraction in vivo and decreases the proliferation of myeloma cells [58]. Then, the antitumor activity of anakinra was mainly mediated by reducing angiogenesis. The administration of anakinra alleviated the levels of CD34-positive blood vessels and significantly reduced the expression of the endothelin 1 gene [57]. Moreover, previous studies have shown that IL-1β elevates the expression of VEGF and VEGF represses the activities of IL-1β [92, 93]. The inhibition of IL-1β by anakinra could obviously suppress the activity of VEGF, leading to an antiangiogenic effect.

Anakinra is usually used as a second-line treatment in rheumatoid arthritis, and subcutaneous injection of anakinra has been approved by the US FDA [94]. However, the antitumor applications of anakinra await further studies.

Previous studies have demonstrated that P2X7 is highly expressed in prostate cancer, pancreatic ductal adenocarcinoma (PDAC), head and neck squamous cell carcinoma, colorectal cancer, and papilloma. When the expression of PX27 is downregulated by siRNA, the metastasis and invasion of prostate cancer cells are notably reduced through the PI3K/AKT and ERK1/2 pathways [59]. In PDAC, P2X7R allosteric inhibitor-treated cells exhibited attenuated tumor proliferation and invasion compared to untreated control cells [60]. In addition, extracellular ATP and BzATP, which have relatively high affinities for P2X7R, further impact cell survival and the complex function of P2X7R [61]. Moreover, P2X7R plays an important role in bone tumor growth and functions [95]. In osteosarcoma, P2X7R was proven to facilitate the growth and matrix invasion of tumor cells, which indicates the potential of P2X7R as a therapeutic target [62]. In another bone cancer, multiple myeloma, the activation of P2X7R was also deemed to affect cell necrosis in the RPMI-8226 cell line [63]. Furthermore, the inhibition of P2X7R can lead to decreased invasiveness in A253 cells, which are derived from an epidermoid carcinoma [64]. Since chronic inflammation is a key factor leading to colorectal cancer, P2X7R has been documented as a regulator in inflammatory responses. In colorectal cancer patients, high expression of P2X7R is significantly associated with tumor size and lymph node metastasis [65]. High expression of P2X7 enhances cancer proliferation, migration, invasion, and angiogenesis. Cancer cells can downregulate the expression of P2X7 to avoid apoptosis and use ATP as an invasion-promoting signal [96]. The activation of P2X7 promotes cancer invasion by releasing cathepsin and MMP-9 [97, 98]. Moreover, the P2X7-dependent release of VEGF promotes angiogenesis and contributes to cancer development [99]. These findings suggest that P2X7R antagonists alter the context of tumor cells, leading to the suppression of cancer progression.

In clinical trials, the safety and tolerability of a P2X7 antagonist were assessed in an open-label, phase I study, in which approximately 65% of patients with basal cell carcinoma showed a decrease in lesion area and the most common adverse event was an allergic reaction occurring at the treatment site [66]. These properties warrant additional studies to evaluate the potential of P2X7 antagonists in the treatment of not only skin cancer but also other malignancies.

Parthenolide is a sesquiterpene lactone compound found in the herb named feverfew, which is used as an anti-inflammatory medicine [100]. While NF-κB has been reported to be a key factor regulating a number of genes that are crucial for tumor invasion and metastasis, parthenolide is considered a potential antitumor therapeutic drug that functions by inhibiting the NF-κB signaling pathway [101]. In gastric cancer, parthenolide significantly inhibits tumor cell growth and downregulates the phosphorylation of NF-κB. During a study of combined therapy with parthenolide and paclitaxel, the survival time of patients with gastric cancer was notably prolonged [67]. In addition, in pancreatic adenocarcinoma, tumor cell growth can be inhibited by parthenolide in a dose-dependent manner. After a higher concentration of parthenolide treatment is administered, internucleosomal DNA fragmentation indicative of apoptosis can be observed [69]. In a study of colorectal cancer models, intraperitoneal injection of parthenolide notably inhibited tumor proliferation and angiogenesis. By focusing on the Bcl-2 family in cancer cells, a parthenolide-mediated cell death signaling pathway was investigated and confirmed to be associated with colorectal cancer cell death [68]. In nasopharyngeal carcinoma, parthenolide induces tumor cell death through the NF-κB/COX-2 pathway. Using COX-2 inhibitors or knocking down COX-2 expression with siRNA or shRNA suppresses cancer stem-like cell phenotypes. Parthenolide exerts an inhibitory effect on NF-κB by suppressing both the phosphorylation of IκB kinase and the degradation of IκBα [70]. The mechanisms involved in the antitumor activity of parthenolide, including the inhibition of NF-κB, activation of JNK, activation of p53, and suppression of STAT3, have attracted great interest. Parthenolide sensitizes cancer cells to TNF-α-induced apoptosis by inhibiting NF-κB and activating JNK [102]. The administration of parthenolide can activate p53, leading to a reduction in cancer cell proliferation [103]. Moreover, parthenolide can inhibit the activation of STAT proteins by blocking their tyrosine phosphorylation, which is indispensable for STAT translocation into the nucleus and target gene activation [104].

In practical use, the low solubility and bioavailability of parthenolide limit its potential [105]. However, creating synthetic analogs of parthenolide may be a novel way to address this problem [106]. Currently, a clinical trial of parthenolide is being performed in allergic contact dermatitis [107]. Therefore, additional studies are required to exploit parthenolide as a novel antitumor drug.

Canakinumab is a human monoclonal antibody targeting IL-1β but not IL-1α. In 2009, canakinumab was authorized by the US Food and Drug Administration and European Medicines Agency as a treatment for cryopyrin-associated periodic syndromes [108]. A randomized, double-blinded trial found that compared with controls, canakinumab at a dosage of 150 mg every 3 months led to a notable reduction in the rate of recurrent cardiovascular events [109]. When cancer is considered, canakinumab still deserves recognition. During a randomized, double-blinded, placebo-controlled trial of patients with lung cancers and atherosclerosis, researchers found that canakinumab could significantly decrease lung cancer mortality by targeting the IL-1β innate immunity pathway. It is worth mentioning that this antitumor effect is mostly detected in patients with lung adenocarcinoma or poorly differentiated large cell cancer, whereas meaningful assessments of the effects on patients with small cell lung cancers or squamous cell carcinomas have rarely been performed [78]. The chronic use of aspirin can reduce mortality in colorectal cancer and lung adenocarcinomas due to its anti-inflammatory activity [110, 111], and canakinumab is theorized to combat cancer in a similar way, according to its function of inhibiting the inflammasome [78].

Currently, the application of canakinumab as an antitumor drug is mainly focused on lung cancer. Canakinumab is being studied in phase III clinical trials in non-small cell lung cancer to evaluate its tolerability and efficacy compared with those of a placebo. Consequently, the completion of the clinical trials is warranted to determine whether canakinumab can be used safely and effectively in cancer treatment.

Andrographolide is a labdane diterpenoid that has been isolated from the stem and leaves of Andrographis paniculata [112]. Numerous studies have validated the facts that andrographolide can inhibit cell invasion and induce cell death in various types of cancer cells. A recent study showed that andrographolide significantly reduces tumor cell proliferation at both the early stage and advanced stage of insulinoma by targeting the TLR4/NF-κB signaling pathway [71]. In addition, in colon cancer, andrographolide represses cell proliferation, elevates cell apoptosis, and activates caspase-3/9 in SW620 human colon cancer cells by inhibiting NF-κB, TLR4, MyD88, and MMP-9 signaling activation [72]. Among chemotherapeutic drugs, 5-fluorouracil (5-Fu) is the one most commonly used in colorectal cancer. Andrographolide can promote the 5-Fu-induced antitumor effect by repressing the level of phosphorylated cellular-mesenchymal to epithelial transition factor [73]. In colitis-associated cancer, andrographolide inhibits the NLRP3 inflammasome, protecting mice against dextran sulfate sodium-induced colon carcinogenesis [74]. In breast cancer, andrographolide suppresses breast cancer-induced osteolysis by inhibiting the NF-κB and ERK signaling pathway at a relatively low dose and by promoting apoptosis at a relatively high dose. Its antitumor activity correlates with the downregulation of the NF-κB signaling pathway [75, 76]. Moreover, andrographolide reduces proliferation and increases cell apoptosis by downregulating the protein expression of TLR4 and NF-κB in multiple myeloma [77]. The antitumor mechanisms of andrographolide include the inhibition of the NF-κB pathway [113], suppression of cyclins and cyclin-dependent kinases [114], and activation of the p53 protein [114], leading to reductions in cancer cell proliferation, invasion, and angiogenesis.

Clinical trials of andrographolide have mainly focused on inflammatory diseases such as acute upper respiratory tract infections [115, 116], and its antitumor activity has been demonstrated only in vitro. Therefore, more studies are required to investigate its application in cancer treatment.

Overall, clinical application was limited to only anakinra and thalidomide, and other drugs are still under assessment in clinical trials. All of these drugs inhibit the production and activation of inflammasome-associated molecules such as P2X7R, IL-1, NF-κB, and caspase-1, leading to the suppression of the inflammasome. As mentioned above, the antitumor mechanisms of these drugs involve the regulation of the expression of p53, NF-κB, STAT, and VEGF, leading to the suppression of tumor cell proliferation, metastasis, invasion, and angiogenesis. However, the direct interactions of inflammasome inhibitors involved in repressing cancer development are not yet known. Further studies are needed to explore the mechanisms in a more explicit way.