Neuroprotective effects of andrographolide derivative CX-10 in transient focal ischemia in rat: Involvement of Nrf2/AE and TLR/NF-κB signaling.

Ischemic stroke is a major cause of mortality and disability worldwide. To date there is no ideal effective treatment. 3, 14, 19-triacetyl andrographolide (CX-10) is a new molecule entity derived from andrographolide. The aim of the present study was to evaluate the neuroprotection of CX-10 against experimental cerebral ischemia. The anti-inflammation of CX-10 was screened using LPS-induced inflammation in vitro and in vivo. Rats were subjected to 1.5 h of middle cerebral occlusion (MCAO) and then reperfusion for 72 h. The infarct size was evaluated by TTC staining, and the behavioral disturbance was evaluated, and inflammatory cytokines and anti-oxidant enzymes in brain tissues were examined. Western blot was used to analyze the expression of proteins. The results showed that CX-10 exerted potent anti-inflammatory and anti-oxidation activities, which significantly inhibited LPS-induced TNF-α and NO release, lowered TNF-α and IL-1ß levels in the brain, meanwhile increased activities of SOD, CAT and GSH-P × . The effect of CX-10 was equivalent to that of dexamethasone, and was obviously superior to that of andrographolide. CX-10 exhibited a neuroprotective effects, manifested as reducing infarct size, improving neurological function and reducing motor impairments. Furthermore, western blot analysis revealed that treatment with CX-10 down-regulated the expression of TLR4, NF-κB, TNF-α and iNOS, induced Nrf2 and HO-1 expression. Overall, CX-10 has a favorable neuroprotection in ischemic brain injury. The mechanism may involve inhibition of TLR4/NF-κB signaling pathway and upregulation of Nrf2/ARE signaling pathway. All these indicated that CX-10 is likely to be a promising agent for ischemic stroke.

LWJ-M30, a conjugate of DM1 and B6, for the targeted therapy of colorectal cancer with improved therapeutic effects.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide as well as a significant cause of mortality. The conventional treatment could cause serious side effects and induce drug resistance, recurrence and metastasis of cancers. Hence, specific targeting of cancer cells without affecting the normal tissues is currently an urgent necessity in cancer therapy. The emerging of peptide-drug conjugates (PDC) is regarded as a promising approach to address malignant tumors. LWJ-M30, a conjugate of DM1 and B6 peptide, targeted transferrin receptors (TfRs) on the surface of the CRC cells, showing a powerful anti-cancer effect. LWJ-M30 significantly inhibited the HCT116 cells proliferation and migration in vitro. LWJ-M30 also dramatically decreased the level of polymeric tubulin, while the disruption of microtubules caused the cell cycle to be arrested in the G2/M phase. LWJ-M30 induced the HCT116 cells apoptosis both in vivo and in vitro. The results in vivo demonstrated that LWJ-M30 could inhibit the HCT116 growth without affecting the mouse body weight. Taking these results together, our data indicated that LWJ-M30 could improve the therapeutic effects of DM1 while reducing the systemic toxicity in normal tissues.

XHL11, a novel selective EGFR inhibitor, overcomes EGFRT790M-mediated resistance in non-small cell lung cancer.

The first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib significantly improved the therapeutic effect in non-small cell lung cancer (NSCLC) patients with EGFR mutation. However, the EGFRT790M mutation occurs and results in acquired resistance. Consequently, mutant selective third-generation EGFR TKIs represented by AZD9291 (Osimertinib) have been developed to offer more effective therapeutic treatment, but the clinical application is limited by the acquired resistance and the high costs. A series of 5-chloropyrimidine-2,4-diamine derivatives were synthesized and screened for in vitro antitumor activity on H1975 and A431 cells. XHL11 showed the strongest antineoplastic activity. Compared to AZD9291, XHL11 suppressed cellular proliferation and colony formation and induced apoptosis in H1975 cells with EGFRL858R/T790M mutation. In addition, XHL11 caused expression changes in EGFR and apoptosis-related pathways. Moreover, oral administration of XHL11 suppressed tumor progression in vivo in a H1975 subcutaneous xenograft model. These data demonstrated that XHL11 might be developed as a promising EGFR TKI for the therapeutic use of NSCLC patients.