Phenothiazines and Selenocompounds: A Potential Novel Combination Therapy of Multidrug Resistant Cancer

Abstract

Background/Aim: Phenothiazines constitute a versatile family of compounds in terms of biological activity, which have also gained a considerable attention in cancer research. Materials and Methods: Three phenothiazines (promethazine, chlorpromazine and thioridazine) have been tested in combination with 11 active selenocompounds against MDR (ABCB1-overexpressing) mouse T-lymphoma cells to investigate their activity as combination chemotherapy and as antitumor adjuvants in vitro with a checkerboard combination assay. Results: Seven selenocompounds showed toxicity on mouse embryonic fibroblasts, while three showed selectivity towards tumor cells. Two compounds showed synergism with all tested phenothiazines in low concentration ranges (1.46-11.25 μM). Thioridazine was the most potent among the three phenothiazines. Conclusion: Phenothiazines belonging to different generations showed different levels of adjuvant activities. All the tested phenothiazines are already approved medicines with known pharmacological and toxicity profiles, therefore, their use as adjuvants in cancer may be considered as a potential drug repurposing strategy.

Cyano- and Ketone-Containing Selenoesters as Multi-Target Compounds against Resistant Cancers

“…The ketone derivatives have been designed as derivatives of the potent oxoselenoesters previously reported [ 15 , 16 , 17 , 18 ], attempting to improve their activity and selectivity. The compounds published in these works were the Se-(2-oxopropyl) 4-clorobenzoselenoate (compound 9), the Se-(3,3-dimethyl-2-oxobutyl) 4-clorobenzoselenoate (compound 10), and the Se-(3,3-dimethyl-2-oxobutyl) 3,5-dimethoxybenzoselenoate (compound 11).…”

“…The compounds published in these works were the Se-(2-oxopropyl) 4-clorobenzoselenoate (compound 9), the Se-(3,3-dimethyl-2-oxobutyl) 4-clorobenzoselenoate (compound 10), and the Se-(3,3-dimethyl-2-oxobutyl) 3,5-dimethoxybenzoselenoate (compound 11). Cyanoselenoesters have been designed as a variation of the ones included in a previous patent of the group [ 18 ], with the same improvement aim of the activity showed by the initial cyanoselenoesters included in this patent.…”

“…Seeing the noteworthy activity in previous works [ 15 , 16 , 17 , 18 ] shown by derivatives that contain halogens, we have considered herein different halogenated substituents (bromine, fluorine, trifluoromethyl, chlorine), as well their polysubstitution, to determine which ones enhanced the biological effects. Additionally, compounds with a thiophene ring or with a 4- tert -butyl substituent are included to evaluate the activity of compounds that contain heterocycles or electron-donating substituents, respectively.…”

“…It has been confirmed that selenium compounds synergistically enhance the activity of anticancer drugs when they are administered in combination [ 17 ]. Furthermore, as a drug-repurposing approach, phenothiazines with a known pharmacological and toxicity profile were combined with the previously mentioned selenoanhydride and selenoester, and several Se-compounds exhibited synergistic activity in combination with promethazine, chlorpromazine, and thioridazine [ 18 ]. The synergistic effects observed suggest that selenium compounds are able to reverse MDR and potentiate the activity of reference anticancer drugs or compounds with well-defined anticancer activity.…”

Oncoimmunology Meets Organs-on-Chip

“…Single agent-based strategies are often insufficient for a successful and complete tumor eradication in cancer patients. Current strategies aim at combining therapies with a second (or even third) drug to amplify anti-tumor responses and/or to broaden the spectrum of responding patients (Bao et al, 2020;Crunkhorn, 2020;GajdÁcs et al, 2020;Iratni and Ayoub, 2020;Jonnalagadda et al, 2020;Karimi et al, 2020;Kawachi et al, 2020;Kim et al, 2020;Mollica et al, 2020;Qian et al, 2020;Song et al, 2020;Yamashita et al, 2020;Zhu et al, 2020). The development of microfluidic devices for oncoimmunology applications based on the use of drug combinations is only beginning to emerge.…”