Anticancer effect of covalent purine-containing EGFR TKI, ZZC4 and its mechanism of action through network pharmacology.

AIMS: Epidermal growth factor receptor (EGFR) has been documented in many malignancies as participating in the progression of cancer cells. Here, we present a novel EGFR tyrosine kinase inhibitor, ZZC4, and examine its effect on cancer cell proliferation, migration, and tumor-bearing xenograft models. MAIN METHODS: The antiproliferative effect of ZZC4 was assessed in vitro by MTT assay, colony formation, and wound healing assay and in vivo with tumor-bearing xenograft nude mice. Further, Western blotting analysis and computational network pharmacology were used to explore and understand the mechanism of ZZC4. KEY FINDINGS: The results showed that ZZC4 potently inhibited the proliferation of lung, breast, and melanoma cells, and was more sensitive to lung cancer cells HCC827, H1975, and breast cancer cell T47D. In vitro findings were corroborated in vivo as results showed the suppressive effect of ZZC4 on HCC827 and H1975 tumor growth. Western blotting analysis confirmed that ZZC4 is an effective inhibitor of the EGFR pathways as it down-regulated p-EGFR, p-Akt, and p-MAPK. Computational molecular docking confirmed the strong binding affinity between ZZC4 and EGFR. Moreover, network pharmacology suggested that ZZC4 might play a suppressive role in the progression of malignancies with EGFR/PI-3K/Akt axis dysregulation or in cancer-related drug resistance. SIGNIFICANCE: Our study showed that ZZC4 is an anticancer drug candidate.

Lung cancer treatment potential and limits associated with the STAT family of transcription factors.

Lung cancer is one of the mortal cancers and the leading cause of cancer-related mortality, with a cancer survival rate of fewer than 5% in developing nations. This low survival rate can be linked to things like late-stage detection, quick postoperative recurrences in patients receiving therapy, and chemoresistance developing against various lung cancer treatments. Signal transducer and activator of transcription (STAT) family of transcription factors are involved in lung cancer cell proliferation, metastasis, immunological control, and treatment resistance. By interacting with specific DNA sequences, STAT proteins trigger the production of particular genes, which in turn result in adaptive and incredibly specific biological responses. In the human genome, seven STAT proteins have been discovered (STAT1 to STAT6, including STAT5a and STAT5b). Many external signaling proteins can activate unphosphorylated STATs (uSTATs), which are found inactively in the cytoplasm. When STAT proteins are activated, they can increase the transcription of several target genes, which leads to unchecked cellular proliferation, anti-apoptotic reactions, and angiogenesis. The effects of STAT transcription factors on lung cancer are variable; some are either pro- or anti-tumorigenic, while others maintain dual, context-dependent activities. Here, we give a succinct summary of the various functions that each member of the STAT family plays in lung cancer and go into more detail about the advantages and disadvantages of pharmacologically targeting STAT proteins and their upstream activators in the context of lung cancer treatment.

F10, a new camptothecin derivative, was identified as a new orally-bioavailable, potent antitumor agent.

Topoisomerases are interesting targets for drug discovery. In the present study, we attached saturated carbon atoms to the 10-position of camptothecin and synthesized 10 new camptothecin derivatives from 10-HCPT or SN-38. The activities of new compounds were evaluated both in vitro and in vivo. The most promising compound F10, 7-ethyl-10-(2-oxo-2-(piperidin-1-yl)ethoxy)camptothecin, inhibited cancer cells growth with the IC50 of 0.002, 0.003, 0.011 and 0.081 µM on Raji, HCT116, A549 and Lovo cells, respectively. Meanwhile, oral administration of F10 remarkably suppressed the HCT116-xenograft tumor growth in the nude-mice model at the dosage of 0.5, 2.0 and 8.0 mg/kg in vivo. Intraperitoneal administration of F10 can completely inhibit Raji-xenograft tumor growth in established NPG mouse model at 2.0 and 4.0 mg/kg. In addition, the minimum lethal doses of F10 and SN-38 in mice by intravenous administration were 80 and 40 mg/kg (or 0.155, 0.102 mmol/kg), respectively. The solubility of F10 reached 9.86 µg/mL in a buffer solution of pH 4.5. The oral bioavailability of F10 achieved 22.4% in mice. The molecular docking model revealed that F10 can interact with topoisomerase I-DNA complex. Our findings indicate that F10 is a new orally-oavailable antitumor agent with potent anticancer effect. Furthermore, attaching a ring hydrophobic moiety to the 10-position of camptothecin provides a favorable approach in the optimization of camptothecin.