Novel anti-cancer drug COTI-2 synergizes with therapeutic agents and does not induce resistance or exhibit cross-resistance in human cancer cell lines

Saman Maleki Vareki; Kowthar Y Salim; Wayne R Danter; James Koropatnick

doi:10.1371/journal.pone.0191766

Novel anti-cancer drug COTI-2 synergizes with therapeutic agents and does not induce resistance or exhibit cross-resistance in human cancer cell lines

PLoS One. 2018 Jan 24;13(1):e0191766. doi: 10.1371/journal.pone.0191766. eCollection 2018.

Authors

Saman Maleki Vareki¹, Kowthar Y Salim², Wayne R Danter², James Koropatnick^{1

3

4

5

6}

Affiliations

¹ Cancer Research Laboratory Program, Lawson Health Research Institute, London, Ontario, Canada.
² Cotinga Pharmaceuticals (formerly Critical Outcome Technologies Inc.), London, Ontario, Canada.
³ Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
⁴ Department of Pathology, Western University, London, Ontario, Canada.
⁵ Department of Oncology, Western University, London, Ontario, Canada.
⁶ Department of Physiology and Pharmacology, Western University, London, Ontario, Canada.

Abstract

Emerging drug-resistance and drug-associated toxicities are two major factors limiting successful cancer therapy. Combinations of chemotherapeutic drugs have been used in the clinic to improve patient outcome. However, cancer cells can acquire resistance to drugs, alone or in combination. Resistant tumors can also exhibit cross-resistance to other chemotherapeutic agents, resulting in sub-optimal treatment and/or treatment failure. Therefore, developing novel oncology drugs that induce no or little acquired resistance and with a favorable safety profile is essential. We show here that combining COTI-2, a novel clinical stage agent, with multiple chemotherapeutic and targeted agents enhances the activity of these drugs in vitro and in vivo. Importantly, no overt toxicity was observed in the combination treatment groups in vivo. Furthermore, unlike the tested chemotherapeutic drugs, cancer cells did not develop resistance to COTI-2. Finally, some chemo-resistant tumor cell lines only showed mild cross-resistance to COTI-2 while most remained sensitive to it.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminoquinolines / therapeutic use*
Animals
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Cisplatin / administration & dosage
Deoxycytidine / administration & dosage
Deoxycytidine / analogs & derivatives
Drug Resistance, Neoplasm
Gemcitabine
Lung Neoplasms / pathology
Mice
Paclitaxel / administration & dosage
Thiosemicarbazones / therapeutic use*
Vinblastine / administration & dosage
Vinblastine / analogs & derivatives
Vinorelbine
Xenograft Model Antitumor Assays

Substances

Aminoquinolines
COTI-2 compound
Thiosemicarbazones
Deoxycytidine
Vinblastine
Paclitaxel
Cisplatin
Vinorelbine
Gemcitabine

Grants and funding

Because this work was supported by unrestricted grants from Critical Outcome Technologies Inc. (now known as Cotinga Pharmaceuticals, Inc.) to James Koropatnick, and Critical Outcome Technologies Inc. provided support in the form of salaries for two of the co-authors [KYS, WRD], further explanation is required. KYS and WRD played no role in the study design, data collection, or decision to publish. However, KYS and WRD reviewed the draft manuscript generated solely by SMV (a research associate supervised solely by JK) and JK, and made suggestions to JK with respect to data analysis and text to be included in the final manuscript. JK accepted, accepted with modification, or rejected those suggestions at his sole and exclusive discretion. JK made those decisions purely on the basis of their verifiability, accuracy, conservative interpretation of results, and suitability for publication in this journal: there was no pressure from those authors or Critical Outcome Technologies, Inc., implicit or explicit, to include/exclude data, analysis, or interpretation of data.