New formulations with royleanone derivatives from Plectranthus spp. to inhibit P-glycoprotein activity

Abstract

Multidrug resistant (MDR) cancer cases continue to increase, such that the search for novel and more effective anti-cancer therapeutics is of high priority. In some MDR cancers, the overexpression of membrane transport proteins, like P-glycoprotein (P-gp), continues to be a major impediment to successful therapy. Plectranthus genus (Lamiaceae), known for their medicinal and therapeutic properties, is a well-known source of bioactive diterpenoids, such as 7α-acetoxy-6β-hydroxyroyleanone (Roy) and 6,7- dehydroroyleanone (DeRoy). Based on in silico molecular docking studies, a small library of semi-synthetic derivates was prepared. The antitumoural activity of the compounds was assessed in resistant human cancer cell lines NCI-H460/R and DLD1-TxR. Cell viability was assessed using MTT assay and cell death induction by Annexin V/PI. Overall, it was demonstrated that three of the abietane diterpenoid analogues induced P-gp inhibition in MDR cancer cell lines, presenting novel selective compounds for the possible treatment of lung and colon cancer. Moreover, Roy and DeRoy nano-formulations were successfully prepared. DeRoy hybrid nanoparticles significantly increased the efficacy of DeRoy in NCI-H460 and NCI- H460/R. Roy, conjugated with oleic acid afforded self-assembly nanoparticles, to improve aqueous solubility and bioavailability of Roy. This new nano formulation did not decrease cell viability of Vero-E6 cells when compared to Roy with potential as a pro-drug delivery system. Currently, top hit derivatives are being prepared into nano-formulations for prospective pharmaceutical use as P-gp modulators.