The anticancer effect of the TLR4 inhibition using TAK‐242 (resatorvid) either as a single agent or in combination with chemotherapy: A novel therapeutic potential for breast cancer

Abstract

Increasing pieces of evidence indicate that inflammatory processes facilitate tumorigenesis; tumor cells simulate the mechanisms by which innate immune cells produce pro‐inflammatory cytokines to exploit them for their own survival and proliferation. Toll‐like receptor 4 (TLR4), which serves as one of the most well‐known receptors on the surface of the immune cells, is often expressed ectopically in the tumor cells resulting in tumor progression, invasion, and chemoresistance. In this study, we examined the anticancer effects of TAK‐242, a small molecule inhibitor of TLR4, on different breast cancer cell lines: MCF7, SKBR3, MDA‐MB‐231, and BT‐474. Our results showed that the TLR4 inhibition, as revealed by the downregulation of TLR4 downstream genes, exerted desirable cytotoxicity on the TLR4‐expressing cells, at least partly, through the downregulation of EGFR and c‐Myc genes. TAK‐242 also inhibited the proliferation of anoikis‐resistant cells and suppressed the clonal growth of the indicated cells. The results of this study propose a mechanistic pathway by which the inhibition of TLR4 using TAK‐242 could augment apoptotic cell death through the alteration of both nuclear factor‐кB‐ and p53‐related apoptosis genes in breast cancer cells, especially cells with overexpression of TLR4. Taken together, this study supports the idea that the activation of inflammatory pathways may have a crucial role in breast cancer progression and the inhibition of TLR4 using TAK‐242, either as a single agent or in combination, seems to be a novel promising strategy that could be clinically available in foreseeable future.

Role of Toll-Like Receptor (TLR)-Signaling in Cancer Progression and Treatment

“…SM934, a derivative of another anti-malarial drug artemensin can inhibit the proliferation and metastasis in breast cancer probably via inhibition of TLR signaling [52]. TAK-242 specifically inhibits TLR-4 by binding to cysteine 747 in the intracellular domain and consequently suppresses the progression of breast cancer [53]. Therapeutic role of SM934, another artemensin derivative has been well documented in inflammatory disease [54], but its role in cancer prevention is still need to be explored.…”

The role of toll‐like receptor 4 (TLR4) in cancer progression: A possible therapeutic target?

“…Furthermore, a GWAS study on primary biliary cirrhosis (PBC) patients has revealed that PDGFB was the only transcript regulated by risk variants of TLR4 signaling (Kim et al, 2014). But more importantly, TLR4/PDGF interactions have been reported in malignant tissues, since they share common ligands (e.g., HIF‐1α) and downstream transcription factors (e.g., c‐Myc) that could potentially cause feedback loops (Han et al, 2016; Moench et al, 2016; Zandi, Kashani, Bashash, et al, 2019).…”

“…Inline, it has been reported that the activation of TLR4 with LPS induced resistance of human colon and pancreatic cancer cells to TRAIL‐induced apoptosis in an NF‐кB‐dependent manner (Beyer et al, 2017; Tang & Zhu, 2012). Besides, it has been revealed that the inhibition of TLR4 using small molecule inhibitor TAK‐242 suppressed NF‐кB‐related antiapoptosis genes BCL‐xL, BCL‐2, and survivin in breast and ovarian cancer cells and led to increased apoptosis (Kashani, Zandi, Bashash, et al, 2019; Zandi, Kashani, Bashash, et al, 2019). In an interesting study, it was shown that after treating colon cancer cells with oxaliplatin and 5‐fluorouracil, the stimulation of TLR4 led to the phosphorylation of GSK3β, overexpression of Bcl‐2 family and multidrugs resistance proteins, and significant inhibition of apoptosis (Chung & Kim, 2016).…”

“…It was reported that topical use of TAK‐242 could suppress UV‐induced skin tumorigenesis, emphasizing its potential for preventing tumor progression (Blohm‐Mangone et al, 2018). TAK‐242 has also been used for the treatment of breast and ovarian cancer cells by our team; we selected a panel of cancer cells and showed that the inhibitor could attenuate both invasion and proliferation of breast and ovarian cells (Kashani, Zandi, Bashash, et al, 2019; Zandi, Kashani, Bashash, et al, 2019; Zandi, Kashani, Poursani, et al, 2019). We also demonstrated that its combination with conventional chemotherapeutic agents could intensify their anticancer effects (Kashani, Zandi, Karimzadeh, et al, 2019).…”

Toll‐like receptors (TLRs) in cancer; with an extensive focus on TLR agonists and antagonists

“…16,17 Recently, it became evident that this inhibitor has significant anti-tumor capacity. TAK-242 exerted a favorable effect in ovarian 18 and breast cancer cells 19 through regulating the expression of both NF-κBand p53-dependent apoptotic target genes. TAK-242 also prevented the epithelial-mesenchymal transition of ovarian and breast cancer cells by reducing the enzymatic activity of matrix metalloproteinase 2 and 9.…”