Combined anticancer therapy with imidazoacridinone analogue C-1305 and paclitaxel in human lung and colon cancer xenografts : modulation of tumour angiogenesis

The acridanone derivative 5-dimethylaminopropylamino-8-hydroxytriazoloacridinone (C-1305) has been described as a potent inhibitor of cancer cell growth. Its mechanism of action in in vitro conditions was attributed, among others, to its ability to bind and stabilize the microtubule network and subsequently exhibit its tumour-suppressive effects in synergy with paclitaxel (PTX). Therefore, the objective of the present study was to analyse the effects of the combined treatment of C-1305 and PTX in vivo. In addition, considering the results of previous genomic analyses, particular attention was given to the effects of this treatment on tumour angiogenesis. Treatment with C-1305 revealed antitumor effect in A549 lung cancer cells, and combined treatment with PTX showed tendency to anticancer activity in HCT116 colon cancer xenografts. It also improved tumour blood perfusion in both tumour models. The plasma level of CCL2 was increased and that of PDGF was decreased after combined treatment with C-1305 and PTX. The experimental results showed that the levels of FGF1, TGF-beta and Ang-4 decreased, whereas the levels of ERK1/2 and Akt phosphorylation increased in HCT116 tumour tissue following combined treatment with both drugs. The results of in vitro capillary-like structure formation assay demonstrated the inhibiting effect of C-1305 on this process. Although previous in vitro and in vivo studies suggested a positive effect of C-1305 on cancer cells, combined treatment of HCT116 human colon and A549 lung cancer cells with both PTX and C-1305 in vivo showed that the antitumor activity was restricted and associated with the modulation of tumour angiogenesis

The Effects of Single Nucleotide Polymorphisms in Cancer RNAi Therapies

Tremendous progress in RNAi delivery methods and design has allowed for the effective development of siRNA-based therapeutics that are currently under clinical investigation for various cancer treatments. This approach has the potential to revolutionize cancer therapy by providing the ability to specifically downregulate or upregulate the mRNA of any protein of interest. This exquisite specificity, unfortunately, also has a downside. Genetic variations in the human population are common because of the presence of single nucleotide polymorphisms (SNPs). SNPs lead to synonymous and non-synonymous changes and they occur once in every 300 base pairs in both coding and non-coding regions in the human genome. Much less common are the somatic mosaicism variations associated with genetically distinct populations of cells within an individual that is derived from postzygotic mutations. These heterogeneities in the population can affect the RNAi’s efficacy or more problematically, which can lead to unpredictable and sometimes adverse side effects. From a more positive viewpoint, both SNPs and somatic mosaicisms have also been implicated in human diseases, including cancer, and these specific changes could offer the ability to effectively and, more importantly, selectively target the cancer cells. In this review, we discuss how SNPs in the human population can influence the development and success of novel anticancer RNAi therapies and the importance of why SNPs should be carefully considered