ABSTRACT
Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved the effectiveness of cancer chemotherapy . However, low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent. To tackle these challenges, NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy. All the compounds showed improved sensitivity to paclitaxel (PTX) in P-glycoprotein (P-gp) overexpressing MDR cancer cells. Among them, compound exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that at a dose of 50 mg/kg co-administered with PTX (15 mg/kg), inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors P-gp inhibition. Moreover, Western blot experiments revealed that inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying of multiple mechanisms to reverse MDR in lung cancer.
ABSTRACT
Objective To investigate the expression and clinical significance of multidrug resistance gene(MDR1),multidrug-resistance-associated protein (MRP),lung resistance protein (LRP),glutathione S-transferase-?(GST-?)mRNA in non-small cell lung cancer. Methods From Oct.1996 to Oct.2001,RT-PCR was used to investigate the mRNA expression of the above four genes.We followed up the survival time one by one and calculated the probability of survival. Results The total positive rate of the four multidrug resistance gene was 53.1%,65.3%,67.3%,83.3%.There was a significant difference between the coexpression and the single positive rate( P 0.05).With the increasing expression of the MDR the curves moved to left,the survival time and probability reduced. Conclusion The coexpression of the MRG results in the MDR and affects the prognosis directly.It can be used as a criterion to evaluate the prognosis.