3-hydroxyquinazoline derivatives, analogues of erastin, induce ferroptosis in colorectal cancer cells

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Abstract

In recent years, significant progress has been achieved in the treatment of patients with colon cancer, but in most cases treatment is accompanied by the development of drug resistance. Recently discovered iron-dependent cell death, ferroptosis, makes it a promissing therapeutic target to reduce the recurrence rates. In this study we have examined the effect of 3-hydoxyquinazoline derivatives on ferroptosis induction in two colon cancer cells HCT-116 and DLD-1. The ferroptotic cell death was identified by the level of lipid peroxidation. The level of lipid peroxidation in HCT-116 cells induced by some compounds approached the activity of the reference drug erastin. This scenario changed significantly when the ferroptosis induction was studied in DLD-1 cells. Two 3-hydroxyquinazoline derivatives induced levels of lipid peroxidation in DLD-1 cells that exceeded those of erastin. The preliminary results obtained suggest that three new compounds can be considered as an antitumor agent for the treatment of colon cancer, and also indicate the prospects of further searching for ferroptosis inducers among 3-hydroxyquinazoline derivatives.

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About the authors

V. N. Osipov

N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia

Author for correspondence.
Email: ovn65@yandex.ru
Russian Federation, Kashirskoe shosse 24, Moscow, 115478

A. A. Vartanyan

N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia

Email: ovn65@yandex.ru
Russian Federation, Kashirskoe shosse 24, Moscow, 115478

D. A. Khochenkov

N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia

Email: ovn65@yandex.ru
Russian Federation, Kashirskoe shosse 24, Moscow, 115478

D. V. Gusev

N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia

Email: ovn65@yandex.ru
Russian Federation, Kashirskoe shosse 24, Moscow, 115478

O. V. Fateenkova

I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University)

Email: ovn65@yandex.ru
Russian Federation, ul. Trubetskaya 8/2, Moscow, 119991

D. S. Khachatryan

National Research Center “Kurchatov Institute”

Email: ovn65@yandex.ru
Russian Federation, pl. Akad. Kurchatova 1, Moscow, 123182

L. M. Borisova

N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia

Email: ovn65@yandex.ru
Russian Federation, Kashirskoe shosse 24, Moscow, 115478

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2. Fig. 1. Effect of compound (VIIa) on the induction of ferroptosis in HCT-116 cells: (a) – control – cell growth with 5% DMSO; (b) – cell growth with 1/3 IC50 erastin; (c) – cell growth with 1/3 IC50 of compound (VIIa). Scale bar – 100 µm.

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3. Fig. 2. Quantitative characteristics of the intensity of lipid peroxidation in HCT-116 and DLD-1 cells. K – fluorescence intensity induced by erastin, 1–7 – compounds (VIIa–g), respectively. Data are presented as mean ± standard deviation, p < 0.05.

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4. Scheme 1. Synthesis of 3-hydroxyquinozaline derivatives. Reagents and conditions: i – CH2Cl2/H2O, thiophosgene; ii – AcONa, H2O; iii – NaOH, NH2OH . HCl, H2O; iv – NH2NH2 . H2O, ethanol; v – acetylacetone, ethanol; vi – benzyl chloroacetate, K2CO3, DMF.

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5. Tab. 1, fig. 1

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