S.V. Boichuk1,2, T.V. Ivoilova1, А.R. Galembikova1
1Kazan State Medical University, Kazan
2Russian Medical Academy of Continuing Professional Education, Moscow
Boichuk Sergey V. — Corresponding Member of the Tatarstan Academy of Sciences, Doct. of Sci. (Med.), Professor, Head of the Department of Pathology, Dean of Biomedicine Faculty of the Kazan State Medical University
49 Butlerov Str., Kazan, 420012, Russian Federation., tel.: +7-917-397-80-93, (843) 236-72-63, e-mail: boichuksergei@mail.ru, SPIN-code: 8058-6246, Author ID: 130120, ORCID ID: 0000-0003-2415-1084
Abstract. The development of resistance of malignant tumors to chemotherapy is currently considered as one of the main factors of poor prognosis in most patients with cancer, especially advanced and recurrent forms. Among the broad spectrum of molecular mechanisms of secondary resistance of tumors to anti-cancer agents, special attention is paid to general biological (i.e. universal) mechanisms, including those aimed at enhancing the excretion of drugs from tumor cells by increasing activity in them ABC (ATP-binding cassette)-transporters. We showed here that some of tyrosine kinase inhibitors (TKIs) are able to enhance the effect of chemotherapy drugs and enhance sensitivity of chemoresistant cancer cells with various origins (breast cancer, osteosarcoma, etc.) to doxorubicin, paclitaxel, etc. Among all the studied TKIs, lapatinib was found as the most effective one and significantly increased cytotoxicity of doxirubicin in all cancer cell lines included in present study. This effect was due to the ability of lapatinib to disrupt the excretion of chemotherapeutic agents from cancer cells by inhibiting the function of ABC-transporters, which in turn induced the apoptotic cell death of cancer cells. Considering the fact that the excretion of doxorubicin and mitoxantrone from cells might be due to different types of ABC-transporters (ABCB1 and ABCG2, respectively), our data indicates the ability of lapatinib to inhibit the activity of 2 main types of ABC transporters in cancer cells. Thus, lapatinib represents TKI, which is to enhance sensitivity of broad spectrum of chemoresistant cancer cells to chemotherapeutic drugs by disrupting their excretion, which in turn raises will create the prerequisites for an in-depth study of the effectiveness of the aforementioned combinations of anti-cancer drugs in preclinical and clinical settings.
Key words: lapatinib, doxorubicin, multidrug resistance, ABC-transporters, receptor tyrosine kinase inhibitors, synergism, apoptosis.