Inhibition of Stat3 by peptide aptamer rS3-PA enhances growth suppressive effects of irinotecan on colorectal cancer cells

Abstract

Cytotoxic agents, alone or in combination, are being used in the treatment of colorectal cancer. Despite progress in the therapeutic regimes, this common malignancy is still the cause of considerable morbidity and mortality, and further improvements are required. Cancer cells often exhibit intrinsic resistance against chemotherapeutic agents or they develop resistance over the time of treatment. Several mechanisms have been made responsible, e.g., drugs may fail to reach tumor cells or drugs may fail to elicit cytotoxicity. The molecular characterization of drug resistance in cancer cells may lead to strategies to overcome it and enhance the sensitivity to chemotherapy. Irinotecan is one of the main treatments of colorectal cancer; it is converted into its active metabolite SN38 and acts as a topoisomerase I inhibitor. Inhibition of this enzyme prevents DNA relegation following uncoiling. Irinotecan has been used as a chemotherapeutic agent either as a single agent or in combination with 5-fluorouracil and targeted therapies directed against the epidermal growth factor receptor, such as cetuximab. The transcription factor signal transducer and activator of transcription 3 (Stat3) is a member of the signal transducer and activator of transcription protein family. Its persistent activation is found in tumor cells and has been associated with drug and radiation resistance. The treatment of colorectal cancer cells with irinotecan leads to senescence or apoptosis following DNA double-strand break induction. This process is impaired by the activation of Stat3. We have derived a Stat3 specific peptide aptamer [recombinant Stat3 inhibitory peptide aptamer (rS3-PA)] that recognizes the dimerization domain of Stat3 and effectively inhibits its function. The delivery of rS3-PA into colon cancer cells and the resulting inhibition of Stat3 strongly enhanced the cytotoxic action of SN38. These data show that the targeted inhibition of Stat3 decreases drug resistance and enhances SN38-mediated cell death. The combination of these agents has a potent antitumor effect and could become beneficial for the treatment of patients with colorectal cancer.

Lumbar puncture-administered resveratrol inhibits STAT3 activation, enhancing autophagy and apoptosis in orthotopic rat glioblastomas

“…Interestingly, STAT3 signaling was unevenly inactivated in the tumor tissues, and regions showing STAT3 inhibition exhibited extensive cell death. The roles of STAT3 signaling in suppressing apoptosis and autophagy in cancer cells have been well documented [ 30 , 31 ]. For this reason, the cell death in those regions may be, at least in part, the biological consequence of resveratrol-mediated STAT3 inactivation.…”

Two decades of research in discovery of anticancer drugs targeting STAT3, how close are we?

“…rS3-PA was shown to reduce STAT3 phosphorylation without any effect on STAT1 phosphorylation (Borghouts, et al, 2012). Additionally, the use of rS3-PA together with irinotecan augmented its cytotoxic effect on colon cancer cell lines (Weber, et al, 2012). While rS3-PA was successful at reducing Tu-9648 glioma xenograft tumors in mice, it had limited systemic stability and its effects were transient and declined a few hours after administration (Borghouts, et al, 2012).…”

Inhibition of STAT3 signaling as critical molecular event in HUC-MSCs suppressed Glioblastoma Cells

“…STAT3 proteins suppress antitumor immunity and accelerate tumor progression. STAT3 activation has been observed in many human cancers, including breast, melanoma, and thyroid cancer 50 , 51 . Evidence points to STAT3 playing a critical role in GBM development and progression 52 , and its transcriptional activation is regulated by IL-6-mediated JAK2 27 .…”