Biology session

The efficacy of drugs used to treat malignancies often hampered by the emergence of the so-called multidrug resistance (MDR). Cancer cells with MDR phenotype overexpress a transmembrane protein, P-glycoprotein (Pgp, ABCB1, MDR1) which belongs to the ATP Binding cassette (ABC) transporter superfamily. This efflux pump can recognize and transport a numerous, structurally unrelated compounds from the cytoplasm to the extracellular space. Widely used, conventional anti-cancer agents like doxorubicin, vinblastine, vincristine, paclitaxel and new, promising drugs like tyrosine kinase inhibitors (TKI) are considered strong substrates of Pgp. After the attempts of direct Pgp inhibition are failed in the clinical phase, a new strategy had to be established. One possibility can be the use of the MDR-selective compounds. Our group identified and characterized MDR-selective molecules with paradox toxicity against Pgp overexpressing multidrug resistant cancer cells. Surprisingly, when we use an MDR-selective compound below toxic concentration the resistant cells can be “reprogrammed” to become sensitive again by decreasing the Pgp expression. These “reprogrammed” cells are regaining their sensitivity to chemotherapy and their Pgp expression is equal to endogenous levels. My aim was the understanding of this process using the Pgp-negative MES-SA and Pgp-positive MES-SA/Dx5 (established by continuous drug selection in doxorubicin) uterine sarcoma cell line pair. We proved that this phenotype switch (from resistant to sensitive) caused by the MDR-selective molecules can be very rapid as against our original theory, and it can happen in days following only a single-dose treatment. In my thesis I will explain the effects of different reprogramming strategies (short-term high-dose, long-term low-dose or continuous low-dose) and epigenetic inhibitors on this phenotype switch. Our results are also suggested that even drug-naïve (never treated) cancer cells can obtain MDR phenotype due to high Pgp expression in days. Interestingly, this rapidly acquired drug resistance seems to be reversible suggesting the involvement of epigenetic regulation in the process.