Enhanced proliferation inhibition and apoptosis in glioma cells elicited by combination of irinotecan and imatinib.

Glioma is a kind of lethal malignant tumor, and lacks efficient therapies. Combination therapy has been claimed to be a promising approach to combat cancer, due to its increased anti-cancer effects and reduced side effects. This study aimed to investigate the anti-cancer effect and mechanism of combining imatinib with irinotecan or its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). First, we found that this drug combination exerted synergistic antitumor effects against glioma in vitro and in vivo. In addition, flow cytometry results proved that the SN-38-induced apoptosis was further enhanced by imatinib, and similar results were observed by determining the protein expression levels of apoptosis biomarkers. Interestingly, p53 expression was elevated by the SN-38 mono-treatment, and was not further increased after the co-treatment; besides, knockdown of p53 could only reduce the expression of cleaved-PARP partially, and weaken the enhanced proliferation inhibition induced by SN-38 plus imatinib, indicating that there might be other factors involved in the synergistic effects besides p53. Meanwhile, the markedly elevated p21 expression was observed only in the combination group, instead of the mono-treated groups. According to the results of p21 knockdown, we found that p21 was also required for the synergistic inhibitory effects. Moreover, we explored and ruled out the possibility of imatinib enhancing the sensitivity of irinotecan by inhibiting drug efflux pumps. Thus, our findings collectively suggest that combining irinotecan with imatinib could be a promising new strategy to fight against glioma.

SHC004-221A1, a novel tyrosine kinase, potently inhibits T315I mutant BCR-ABL in chronic myeloid leukemia.

Although judicious use of tyrosine kinase inhibitors that target BCR-ABL constitutes an effective strategy for the control of chronic myeloid leukemia (CML), drug resistance is observed due to kinase domain mutations, among which a major one is BCR-ABLT315I. In this study, we identified SHC004-221A1 as a potent inhibitor of T315I and other BCR-ABL mutants. Biochemical assays demonstrated that SHC004-221A1 has an inhibitory effect on all selected BCR-ABL mutants. In vitro studies showed that SHC004-221A1 inhibited the proliferation of tumor cell lines carrying native and T315I mutant BCR-ABL. Signaling pathway analysis revealed that SHC004-221A1 inhibited the phosphorylation of STAT5 and CrkL, which contributed to the apoptosis of CML cells. In vivo studies indicated that SHC004-221A1 suppressed BCR-ALBT315I-driven tumor growth in mice. Taken together, the results of this study suggested that SHC004-221A1 may be a promising BCR-ABLT315I inhibitor for the treatment of CML.

Cell penetrating peptides from agglutinin protein of Abrus precatorius facilitate the uptake of Imatinib mesylate.

Targeted drug delivery is of paramount importance for cancer patients. Cell penetrating peptides (CPPs) have emerged as potent vehicles for this purpose. Herein, we demonstrate CPP- like properties of two peptides: NH2-SGASDDEEIAR-COOH (SR11) and NH2-ICSSHYEPTVRIGGR-COOH (IR15), derived from the tryptic digest of Abrus precatorius agglutinin. Both IR15 and SR11 were found to be non-toxic at lower doses (up to 50 µg/ml). These two peptides entered into HeLa cells through lipid raft-mediated endocytosis within 15 min and penetrated the nuclear membrane in 60 min of incubation. Co-treatment of peptides (20 µg/ml) and Imatinib (5 µM) in HeLa cells increased uptake of the drug by ∼ 55% and lowered the IC50 value to one-third in comparison to the drug added exclusively. However, co-treatment of TAT peptide (standard CPP) did not alter the Imatinib uptake significantly. In summary, we have identified two novel CPPs from tryptic digest of Abrus agglutinin which increased the cellular uptake of Imatinib upon co-administration. Further studies may result in deciphering a novel mode of drug delivery.