Alantolactone selectively suppresses STAT3 activation and exhibits potent anticancer activity in MDA-MB-231 cells

Abstract

The important goal of cancer drug discovery is to develop therapeutic agents that are effective, safe, and affordable. In the present study, we demonstrated that alantolactone, which is a sesquiterpene lactone, has potential activity against triple-negative breast cancer MDA-MB-231 cells by suppressing the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Alantolactone effectively suppressed both constitutive and inducible STAT3 activation at tyrosine 705. Alantolactone decreased STAT3 translocation to the nucleus, its DNA-binding, and STAT3 target gene expression. Alantolactone significantly inhibits STAT3 activation with a marginal effect on MAPKs and on NF-κB transcription; however, this effect is not mediated by inhibiting STAT3 upstream kinases. Although SHP-1, SHP-2, and PTEN, which are protein tyrosine phosphatases (PTPs), were not affected by alantolactone, the treatment with a PTP inhibitor reversed the alantolactone-induced suppression of STAT3 activation, indicating that PTP plays an important role in the action of alantolactone. Finally, alantolactone treatment resulted in the inhibition of migration, invasion, adhesion, and colony formation. The in vivo administration of alantolactone inhibited the growth of human breast xenograft tumors. These results provide preclinical evidence to continue the development of alantolactone as a STAT3 inhibitor and as a potential therapeutic agent against breast cancer.

Anticancer Natural Compounds as Epigenetic Modulators of Gene Expression

“…Isoprenoid Ascochlorin was found to inhibit growth and invasion of hepatocellular carcinoma by targeting STAT3 signaling through the induction of protein inhibitor of activated STAT3 [130]. A sesquiterpene lactone Alantolactone was shown to selectively suppress the STAT3 activation exhibiting a potent anticancer activity in breast cancer MDA-MB-231 cells and colorectal HepG2 cells [131, 132]. Ethyl acetate extract from Jiedu Xiaozheng Yin was reported to inhibit the proliferation of human hepatocellular carcinoma cells in vitro and in vivo by suppressing the polycomb complex member BMI1 (also known as polycomb group RING finger protein 4, PCGF4) or RING finger protein 51, RNF51) and CTNNB1 (β-catenin) signaling [133, 134].…”

Arctigenin inhibits STAT3 and exhibits anticancer potential in human triple-negative breast cancer therapy

“…This family, including STATs 1, 2, 3, 4, 5a, 5b, and 6, promote tumor cell survival, proliferation and drug resistance [8]. In cancer, STATs are often constitutively activated in response to the abnormal binding of a large number of hormones and cytokines to their corresponding receptors [9]. Among the STATs, STAT3 is often constitutively actived in various human cancers including mammary of solid carcinoma and hematologic malignancies [10].…”

Niclosamide inhibition of STAT3 synergizes with erlotinib in human colon cancer

“…Cryptotanshinone has previously been observed to possess the most powerful antibacterial, anti-inflammatory, and antitumor effect 34. Alantolactone has an inhibitory effect on cancer cells migration, invasion, adhesion, and colony formation 35. Therefore, we screened the antiproliferative effects of these 4 compounds in human colon cancer cells by MTT assay.…”