Role of Diaphorase in Intracellular Activation of Prodrugs in Targeted Chemotherapy of Cancers



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Abstract

Diaphorase (NQO1, NAD(P)H:quinone oxidoreductase 1) is an important biomarker of the presence and progression of cancer and also plays a key role in the activation of prodrugs used in targeted chemotherapy of tumors. This work aimed to compare data from long-term studies of the role of diaphorase in the intracellular activation of prodrugs used in targeted chemotherapy of oncologic diseases. The review includes data from relevant publications describing the biochemical functions of diaphorase, its role in oncology, and possibilities for increasing the effectiveness of antitumor therapy through induction of this enzyme. Articles published from 2000 to 2025 and indexed in the databases PubMed, ScienceDirect, and eLIBRARY.RU were analyzed. The study used methods of internet analysis, content analysis, and historical and descriptive-analytical approaches. Diaphorase accelerates the two-electron reduction of quinones to hydroquinones, preventing the formation of free radicals whereas simultaneously providing bioreductive activation of a number of cytotoxic drugs. Overexpression of diaphorase in malignant cells makes it possible to use this enzyme as a biocatalytic mechanism for selective delivery and activation of prodrugs, thereby increasing therapeutic effectiveness. The review examines modern enzyme–prodrug strategies, including ADEPT (Antibody-Directed Enzyme Prodrug Therapy), GDEPT (Gene-Directed Enzyme Prodrug Therapy), and PMT (Prodrug Monotherapy), as well as prospects for induction of diaphorase by compounds of the 1,2-dithiole-3-thione class and phytochemical agents. The relationship between NQO1 activity, mitochondrial dysfunction of tumor cells, and initiation of apoptosis is emphasized. Overall, diaphorase is considered a promising molecular target for the development of new bioreductive and mitochondria-targeted antitumor drugs.

About the authors

V. N. Fedorov

Yaroslavl State Medical University; Yaroslavl State Pedagogical University named after K.D. Ushinsky

Author for correspondence.
Email: fedorov.vladimir@hotmail.com
ORCID iD: 0009-0003-1296-1861
SPIN-code: 4245-8787

MD, Dr. Sci. (Medicine), Professor, Head, Scientific Department of the Institute of Pharmacy; Head, Pharmacological Research Department, M.V. Dorogov Center for Pharmaceutical Technology Transfer

Russian Federation, Yaroslavl; Yaroslavl

Vladimir P. Vdovichenko

Grodno State Medical University

Email: vmariposa60@yahoo.com
ORCID iD: 0009-0009-6739-6154
SPIN-code: 4873-5508

MD, Cand. Sci. (Medicine), Assistant Professor, Depart. of Pharmacology

Belarus, Grodno

Michael K. Korsakov

Yaroslavl State Medical University; Yaroslavl State Pedagogical University named after K.D. Ushinsky

Email: mkkors@mail.ru
ORCID iD: 0000-0003-0913-2571
SPIN-code: 2897-2520

Dr. Sci. (Chemistry), Assistant Professor, Head, Depart. of Biochemistry; director, M.V. Dorogov Pharmaceutical Technology Transfer Center

Russian Federation, Yaroslavl; Yaroslavl

Anna A. Romanycheva

Yaroslavl State Medical University; Yaroslavl State Pedagogical University named after K.D. Ushinsky

Email: kai-ren@yandex.ru
ORCID iD: 0000-0002-7931-1711
SPIN-code: 3994-4146

Cand. Sci. (Biology), research associate, Scientific Department of the Institute of Pharmacy; research associate, M.V. Dorogov Pharmaceutical Technology Transfer Center

Russian Federation, Yaroslavl; Yaroslavl

Alena V. Korovina

Yaroslavl State Medical University; Yaroslavl State Pedagogical University named after K.D. Ushinsky

Email: a.korovina@yspu.org
ORCID iD: 0009-0003-5743-6948
SPIN-code: 2266-1112

junior research associate, Scientific Department of the Institute of Pharmacy; research engineer, M.V. Dorogov Pharmaceutical Technology Transfer Center

Russian Federation, Yaroslavl; Yaroslavl

Andrej V. Arshinov

Yaroslavl State Medical University

Email: a_arshinov@mail.ru
ORCID iD: 0000-0002-0297-8163
SPIN-code: 4974-9170

MD, Dr. Sci. (Medicine), Professor, Head, Depart. of Propaedeutics of Internal Diseases

Russian Federation, Yaroslavl

Salavat S. Suleimanov

Saiko Russian-Japanese Medical Center

Email: suleymanov-sh@mail.ru
ORCID iD: 0000-0002-3176-2716
SPIN-code: 9047-1399

MD, Dr. Sci. (Medicine), Professor, directo

Russian Federation, Khabarovsk

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