Identification of anti‐cancer chemical compounds using Xenopus embryos

Abstract

Cancer tissues have biological characteristics similar to those observed in embryos during development. Many types of cancer cells acquire pro‐invasive ability through epithelial–mesenchymal transition (EMT). Similar processes (gastrulation and migration of cranial neural crest cells [CNCC]) are observed in the early stages of embryonic development in Xenopus during which cells that originate from epithelial sheets through EMT migrate to their final destinations. The present study examined Xenopus embryonic tissues to identify anti‐cancer compounds that prevent cancer invasion. From the initial test of known anti‐cancer drugs, AMD3100 (an inhibitor of CXCR4) and paclitaxel (a cytoskeletal drug targeting microtubules) effectively prevented migration during gastrulation or CNCC development. Blind‐screening of 100 synthesized chemical compounds was performed, and nine candidates that inhibited migration of these embryonic tissues without embryonic lethality were selected. Of these, C‐157 (an analog of podophyllotoxin) and D‐572 (which is an indole alkaroid) prevented cancer cell invasion through disruption of interphase microtubules. In addition, these compounds affected progression of mitotic phase and induced apoptosis of SAS oral cancer cells. SAS tumors were reduced in size after intratumoral injection of C‐157, and peritoneal dissemination of melanoma cells and intracranial invasion of glioma cells were inhibited by C‐157 and D‐572. When the other analogues of these chemicals were compared, those with subtle effect on embryos were not tumor suppressive. These results suggest that a novel chemical‐screening approach based on Xenopus embryos is an effective method for isolating anti‐cancer drugs and, in particular, targeting cancer cell invasion and proliferation.

Xenopus Models of Cancer: Expanding the Oncologist’s Toolbox

“…Natural tumour immunity in amphibians has also elucidated immune system interactions ( Banach and Robert, 2017 ), and together with in vitro experiments using extracts ( Deming and Kornbluth, 2006 ), morphogenesis of embryos provides a physiological setting for study of apoptosis ( Ishizuya-Oka, 2011 ; Ito et al, 2012 ). Similarly, key stromal interactions during tumour growth and metastasis have been informed by intra-vital imaging in Xenopus tadpoles ( Haynes-Gimore et al, 2015 ) and by the study of developmental epithelial-to-mesenchymal transition (EMT) events ( Pegoraro and Monsoro-Burq, 2013 ) that are key to malignant tumour invasion ( Tanaka et al, 2016 ). Finally, tadpoles and adult frogs contribute to our understanding of genetic influences on tumorigenesis through induced-tumour-like-structures (ITLSs) ( Wallingford, 1999 ) and the use of a new era of genetically engineered Xenopus models (GEXM) ( Naert et al, 2017 ).…”

“…Furthermore, monitoring developmental events such as tadpole blood and lymphatic formation can be used to screen chemical libraries for anti-angiogenic activity ( Kalin et al, 2009 ), and a transgenic Xenopus reporter model now exists with expression of GFP in both blood and lymphatic vasculature under the xFlk1 promoter ( Ny et al, 2005 , 2013 ) simplifying such analysis even further. Additionally, gastrulation and neural crest migration critically require transient EMT events, and inhibition of the associated cell movements provides an initial in vivo assay to identify compounds that may also inhibit invasion and proliferation of several types of cancer ( Tanaka et al, 2016 ). The large numbers, accessibility and rapid and robust development of embryos have earned Xenopus worldwide credibility in developmental biology; these same attributes are now valid for novel pharmacological screening approaches and are likely be utilised further in the future ( Schmitt et al, 2014 ).…”

Tumor Immunology Viewed from Alternative Animal Models—the Xenopus Story

“…An innovative application in Xenopus is the use of healthy embryos for initial anti-cancer drug screens, which subsequently are tested in mouse cancer models [31]. In this method, beneficial drugs are identified based on whether they disrupt normal development and thus may also have some anti-cancer properties.…”

“…In this method, beneficial drugs are identified based on whether they disrupt normal development and thus may also have some anti-cancer properties. Using this approach, the researchers were able to successfully identify and test drugs that disrupt cancer cell proliferation and metastasis [31]. However, it would be advantageous to also screen prospective drugs on specific tumor types or to gain more insights on their specificity and potency.…”

Application of Neural Networks in Diagnostics of Chemical Compounds Based on their Infrared Spectra

“…The literature describes attempts of solving the problem of identification of the process [12][13][14][15]; however the focus was made on identifying segments of structures, rather than on complete individual substances. The authors also proposed a pioneering approach of identification of chemical compounds employing interdependences occurring in infrared spectra.…”