Targeting STAT-3 signaling pathway in cancer for development of novel drugs: Advancements and challenges

Abstract

Signal transducers and activators of transcription 3 (STAT-3) is a transcription factor that regulates the gene expression of several target genes. These factors are activated by the binding of cytokines and growth factors with STAT-3 specific receptors on cell membrane. Few years ago, STAT-3 was considered an acute phase response element having several cellular functions such as inflammation, cell survival, invasion, metastasis and proliferation, genetic alteration, and angiogenesis. STAT-3 is activated by several types of inflammatory cytokines, carcinogens, viruses, growth factors, and oncogenes. Thus, the STAT3 pathway is a potential target for cancer therapeutics. Abnormal STAT-3 activity in tumor development and cellular transformation can be targeted by several genomic and pharmacological methodologies. An extensive review of the literature has been conducted to emphasize the role of STAT-3 as a unique cancer drug target. This review article discusses in detail the wide range of STAT-3 inhibitors that show antitumor effects both in vitro and in vivo. Thus, targeting constitutive STAT-3 signaling is a remarkable therapeutic methodology for tumor progression. Finally, current limitations, trials and future perspectives of STAT-3 inhibitors are also critically discussed.

Evaluation of selected IL6/STAT3 pathway molecules and miRNA expression in chronic obstructive pulmonary disease

“…In Gp 130 Y757F mutant macrophages, the induction of transcriptional repressor can inhibit inflammatory gene responses in STAT-3 signaling by IL-6 50 . Therefore, efficient anti-inflammatory feedback can be stimulated with continuous Gp 130 and STAT-3 activation in SOCS3-deficient macrophages 51 .…”

Leukemia Inhibitory Factor: An Important Cytokine in Pathologies and Cancer

“…Raddeanin A is an attenuator of STAT3 signaling that has been investigated in many cancers as a potential drug for reversal of chemotherapy resistance [ 184 , 185 ]. Many additional agents that act by directly or indirectly reducing STAT3 signaling have been and are currently being investigated, some of which are FDA approved [ 186 , 187 , 188 ].…”

A Brief Update on STAT3 Signaling: Current Challenges and Future Directions in Cancer Treatment

“…For example, danvatirsen, also known as AZD9150 or ISIS 481464, has been shown to reduce STAT3 mRNA and protein levels and block cell proliferation. Additionally, although danvatirsen is unsuitable for systemic administration because of its rapid degradation, similar to other siRNAs and decoy ODNs [55], the agent diminished the STAT3 protein level, thereby inhibiting the growth of subcutaneous xenograft tumors derived from human hepatocellular carcinoma and diffuse large B-cell lymphoma via intradermal and intratumoral injections, respectively [53, 54,56], and it was well tolerated at doses up to 30 mg/kg/week for 6 weeks in monkeys [57]. Critically, tumor biopsy samples from danvatirsen-treated patients have shown that its uptake was observed mainly in cells of the TME (but not cancer cells), suggesting that the clinical benefit was not due to direct tumor cell modulation, but rather through remodeling of the suppressive TME [58].…”

“…Taken together, the aforementioned evidence indicates that although encouraging data were obtained from preclinical studies, the use of OPB compounds as specific STAT3 inhibitors might be limited because of their effects on many signal transduction pathways. Additionally, there have been concerns about the potentially severe toxicities of OPB-51602 and OPB-31121, including susceptibility to opportunistic infections, which may limit their further development [74], reviewed in [55]. However, given the favorable safety profiles of OPB-111077, its combination with other treatment strategies might open a new avenue for future cancer therapy.…”

“…Although some upstream inhibitors have advanced to clinical trials [55,93,94], it has been observed that JAK inhibitors have limitations, including off-target neurological adverse events [55,93]. For instance, earlyphase clinical trials of JAK1/2 inhibitors (e.g., AZD1480) and Src inhibitors (e.g., dasatinib) have revealed limited efficacy or excessive toxicity in cancer patients [93,95].…”