We focused on the genes determining the response of tumor cells to apigenin. Our results do not suggest that the ABC transporters ABCB1 and ABCB5 may play a role in apigenin resistance. Multidrug resistance caused by P-glycoprotein (MDR1/ABCB1) represents a major obstacle to cancer chemotherapy. P-glycoprotein is expressed in many types of tumors, either intrinsically resistant to anticancer drugs or acquiring resistance during chemotherapy [26]. ABCB5 is highly expressed in melanoma [23] and confers multidrug resistance to anthracyclines and taxanes [24,27]. This ABC transporter can also be found in other tumor types and its expression is correlated with the stem cell marker CD133 [25]. The sensitivity of multidrug-resistant cells expressing ABCB1 or ABCB5 to apigenin implies that apigenin may improve the success of tumor treatment. , which no longer respond to standard anticancer drugs. BCRP/ABCG2 is another ABC transporter mediating MDR and relevant to patients with worse treatment outcomes. A lack of correlation of log10IC50 values ​​for apigenin was observed not only with ABCB1 and ABCB5, but also with ABCG2 (data not shown). This indicates that the most clinically relevant ABC transporters do not play a role in tumor cell resistance to apigenin. Although apigenin is not a P-glycoprotein substrate, it is capable of inhibiting the transport of other P-glycoprotein substrates and modulating drug resistance. [28]. Apigenin can bind to P-glycoprotein without being transported. Apigenin binding disrupts outward transport of substrates, leading to increased intracellular accumulation of anticancer drugs and enhanced cell killing, as shown by doxorubicin in resistant uterine sarcoma (MES-SA/Dx5) cells [ 29]. Additionally, a...... middle of paper ......n log10IC50 values. Tubulin is a well-known target for established drugs such as Vinca alkaloids or taxanes (67). Apigenin also interacts with tubulin and disrupts microtubules (68). These data correspond well to an association between TTLL9 expression and cellular response to apigenin and it can be hypothesized that the microtubule machinery could be a determinant of apigenin sensitivity in cancer cells. Summarizing our results and those of other authors, it is evident that apigenin exerts cytotoxic activity toward cancer cells through multiple rather than single mechanisms (Figure 4). Phytochemicals are known to frequently exert multiple functions (69). During the evolution of life, bioactive compounds with multifactorial modes of action to deter viruses, bacteria or herbivores were superior to monospecific substances, which can easily be prone to the development of resistance..