The novel toluidine sulphonamide EL102 shows pre-clinical in vitro and in vivo activity against prostate cancer and circumvents MDR1 resistance

• Published in: British journal of cancer 2013-10, Vol.109 (8), p.2131-2141
• Main Authors: Toner, A P, McLaughlin, F, Giles, F J, Sullivan, F J, O'Connell, E, Carleton, L A, Breen, L, Dunne, G, Gorman, A M, Lewis, J D, Glynn, S A
• Format: Article
• Language: English
• Subjects: 692/699/67/1059/2326; 692/699/67/1059/99; 692/699/67/589/466; Androgens; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; Cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Resistance; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Epidemiology; Humans; Male; Medical research; Medical sciences; Metastasis; Mice; Microtubules - drug effects; Microtubules - metabolism; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nephrology. Urinary tract diseases; Oncology; Pharmaceuticals; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Radiation; Random Allocation; Sulfonamides - administration & dosage; Sulfonamides - pharmacology; Taxoids - administration & dosage; Toluidines - administration & dosage; Toluidines - pharmacology; Translational Therapeutics; Tubulin - metabolism; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.537

Background: Taxanes are routinely used for the treatment of prostate cancer, however the majority of patients eventually develop resistance. We investigated the potential efficacy of EL102, a novel toluidine sulphonamide, in pre-clinical models of prostate cancer. Methods: The effect of EL102 and/or docetaxel on PC-3, DU145, 22Rv1 and CWR22 prostate cancer cells was assessed using cell viability, cell cycle analysis and PARP cleavage assays. Tubulin polymerisation and immunofluorescence assays were used to assess tubulin dynamics. CWR22 xenograft murine model was used to assess effects on tumour proliferation. Multidrug-resistant lung cancer DLKPA was used to assess EL102 in a MDR1-mediated drug resistance background. Results: EL102 has in vitro activity against prostate cancer, characterised by accumulation in G2/M, induction of apoptosis, inhibition of Hif1 α , and inhibition of tubulin polymerisation and decreased microtubule stability. In vivo , a combination of EL102 and docetaxel exhibits superior tumour inhibition. The DLKP cell line and multidrug-resistant DLKPA variant (which exhibits 205 to 691-fold greater resistance to docetaxel, paclitaxel, vincristine and doxorubicin) are equally sensitive to EL102. Conclusion: EL102 shows potential as both a single agent and within combination regimens for the treatment of prostate cancer, particularly in the chemoresistance setting.