Abnormal vascularization of solid tumours results in the development of microenvironments deprived of oxygen and nutrients that harbour slowly growing and metabolically stressed cells. Such cells display enhanced resistance to standard chemotherapeutic agents and repopulate tumours after therapy. Here we identify the small molecule VLX600 as a drug that is preferentially active against quiescent cells in colon cancer 3-D microtissues. The anticancer activity is associated with reduced mitochondrial respiration, leading to bioenergetic catastrophe and tumour cell death. VLX600 shows enhanced cytotoxic activity under conditions of nutrient starvation. Importantly, VLX600 displays tumour growth inhibition in vivo. Our findings suggest that tumour cells in metabolically compromised microenvironments have a limited ability to respond to decreased mitochondrial function, and suggest a strategy for targeting the quiescent populations of tumour cells for improved cancer treatment.

Screening and initial characterization of anticancer drugs are typically performed using monolayer cultures of tumor cells. It is well established that such monolayer cultures do not represent the characteristics of 3-dimensional solid tumors. The multicellular tumor spheroid model is of intermediate complexity between in vivo tumors and in vitro monolayer cultures and would be more suitable for drug screening. The authors describe a procedure in which multicellular spheroids are used to screen for compounds that induce tumor cell apoptosis. Multicellular spheroids were generated in 96-well plates, and apoptosis was determined using the M30-Apoptosense ^® enzyme-linked immunosorbent assay method. A Z′ factor of approximately 0.5 was observed for HCT116 colon carcinoma spheroids using staurosporine to induce apoptosis. This procedure is attractive for secondary screening of hits from larger cell-based screens. (Journal of Biomolecular Screening 2008:1-8)

In vitro. bioassay screening of 346 methanol extracts originated from 281 native and cultivated plant species growing in Egypt, and related to 81 families, was carried out for schistosomicidal activity. The extracts were bioassayed at 100 µg/mL on viable Schistosoma mansoni. mature worms in culture medium. Viability of worms was examined after exposure for 24 h, and mortality determined. Negative (DMSO) and positive (praziquantel) controls were used. Of the tested plant extracts, 72 were found to possess reproducible in vitro. antischistosomal activity. These active extracts were further subjected to determination of their LC₅₀ and LC₉₀ values. Strong antischistosomal activity was found in the extracts of 15 species (possessing LC₅₀ ≤ 15 µg/mL), viz. Agave americana. L. var. marginata. Trel. (Agavaceae), A. lophantha. Schiede (Agavaceae), Furcraea selloa. C.Koch. (Agavaceae), Calotropis procera. (Aiton) W.T.Aiton (Asclepiadaceae), Pergularia tomentosa. L. (Asclepiadaceae), Asclepias sinaica. (Boiss.) Muschl. (Asclepiadaceae), Alkanna orientalis. (L.) Boiss. (Boraginaceae), Khaya grandifoliola. DC. (Meliaceae), Swietenia mahogani. (L.) Jacq. (Meliaceae), Pimenta racemosa. (Mill.) J.W.Moore (Myrtaceae), Pinus canariensis. C.Sm. (Pinaceae), Verbascum sinaiticum. L. (Scrophulariaceae), Solanum elaeagnifolium. Cav. (Solanaceae), S. nigrum. L. (Solanaceae), and Brachychiton rupestris. (Lindl.) K.Schum. (Sterculiaceae). These 15 species could represent promising bioactive sources that deserve further investigation, with the aim of finding novel antischistosomal agents. The current study represents the first report on a systematic screening of schistosomicidal activity utilizing a large number of plant species.

A high‐throughput screen of the cytotoxic activity of 2000 molecules from a commercial library in three human colon cancer cell lines and two normal cell types identified the acridine acriflavin to be a colorectal cancer (CRC) active drug. Acriflavine was active in cell spheroids, indicating good drug penetration and activity against hypoxic cells. In a validation step based on primary cultures of patient tumor cells, acriflavine was found to be more active against CRC than ovarian cancer and chronic lymphocytic leukemia. This contrasted to the activity pattern of the CRC active standard drugs 5‐fluorouracil, irinotecan and oxaliplatin. Mechanistic studies indicated acriflavine to be a dual topoisomerase I and II inhibitor. In conclusion, the strategy used seems promising for identification of new diagnosis‐specific cancer drugs. (Cancer Sci 2011; 102: 2206–2213)