Abstract
Multidrug resistance (MDR), for which the mechanisms are not yet fully clear, is one of the major obstacles to cancer treatment. In recent years, signal transducer and activator of transcription 3 (STAT3) were found to be one of the important MDR mechanism pathways. Based on the previous research, zhankuic acid A, B, and C were found to have collateral sensitivity effects on MDR cancer cells, and MDR inhibitory activity of zhankuic acid methyl ester was found to be better than that of its acid. Therefore, we executed a systematic examination of the structure–activity relationship of zhankuic acid methyl ester derivatives to collateral sensitivity in MDR cancer cells. The results showed that compound 12 is the best in terms of chemoreversal activity, where the reversal fold was 692, and the IC50 value of paclitaxel combined with 10 μM compound 12 treatment was 1.69 nM in MDR KBvin cells. Among all the derivatives, methyl ester compounds were found to be better than their acids, and a detailed discussion of the structure–activity relationships of all of the derivatives is provided in this work. In addition, compounds 8, 12, and 26 were shown to influence the activation of STAT3 in KBvin cells, accounting for part of their chemoreversal effects. Our results may provide a new combined therapy with paclitaxel to treat multidrug-resistant cancers and provide a new therapy option for patients.
Highlights
Various advanced cancer therapies have emerged, chemotherapy remains an effective treatment for cancer patients
In multidrug resistance (MDR) research, we found an interesting phenomenon indicating that the MDR inhibitory ability of zhankuic acid methyl ester was better than that of its acid, zhankuic acid, in KBvin cells (Figure 1) [25]
A variety of zhankuic acid-type compounds were selected and gathered from our group based on their structures and available quantity
Summary
Various advanced cancer therapies have emerged, chemotherapy remains an effective treatment for cancer patients. Multidrug resistance (MDR), which occurs during or after treatment in a short period, is one of the obstacles accounting for cancer treatment failure [1,2,3]. There are a number of reasons for the formation of MDR, including irregular metabolism, distribution, and absorption to target cells. As cancer cells develop multidrug resistance, the anti-cancer efficacy of chemotherapeutic drugs decreases, which subsequently leads to cancer metastasis and recurrence [4]. Mechanisms of multidrug resistance have been studied intensively, including drug efflux, growth factors, genetic factors, and increased DNA repair ability [4,5,6,7]. ATP-binding cassette (ABC) proteins, such as P-glycoprotein (P-gp), play important roles in multidrug resistance and have drawn much attention due to their potential for therapeutic usage [8,9]
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