The Role of Self-Nanoemulsifying Drug Delivery Systems of CDODA-Me in Sensitizing Erlotinib-Resistant Non–Small Cell Lung Cancer

Abstract

We have investigated the effects of combination treatment involving ERL (erlotinib) with a glycyrrhetinic acid analog, CDODA-Me in overcoming ERL resistance, providing efforts to improve the oral bioavailability of this treatment using self-nanoemulsifying drug delivery systems (SNEDDS). A Qbd (quality-by-design) approach was used to prepare CDMS (CDODA-SNEDDS, 2 μM), which was characterized using surface response methodology to optimize drug content, particle size, and drug release. CDMS/ERL combinations showed synergism in wild-type and resistant H1975 and HCC827 cell lines with combination index values less than 1. Increased apoptosis, mitochondrial membrane potential depletion, and enhanced intracellular ROS levels were also observed in combination therapy. Western blot analysis showed that combination therapy inhibited phosphorylation of epidermal growth factor receptor (EGFR) (p < 0.01 in all cell lines) and Met receptor tyrosine kinase (MET) (p < 0.01 in all cell lines). In vivo, the relative bioavailability of CDMS increased significantly from 22.13 to 151.76 μg/mL compared to the dosing of oral suspension (dose equivalent). Our results demonstrate that combination therapy involving ERL and CDODA-Me overcomes resistance through dual inhibition of p-EGFR and p-MET leading to the induction of apoptosis, intracellular ROS accumulation, and decreased mitochondrial potential. Furthermore, CDMS improved the oral bioavailability of CDODA-Me.

Synergistic effects of methyl 2-cyano-3,11-dioxo-18beta-olean-1,-12-dien-30-oate and erlotinib on erlotinib-resistant non-small cell lung cancer cells

“…Combination treatment with 2 μM CDODA-Me for all TKIs is shown in Table 2 , where 2 μM CDODA-Me is an adequate concentration to yield the highest degree of synergism [ 12 ]. The 4 μM ERL was selected for treatment in all subsequent assays.…”

“…Combining these two drugs presented synergistic negative effects on DNA replication and cell proliferation while promoting oxidative stress. This work adds to our existing research in exploring potential chemo sensitizing agents in drug resistant tumor models [ [12] , [61] , [62] , [63] ].…”

“…Resistant cells were developed according to a previously described method [ 13 ], with exposure to increased concentrations of ERL over 12 months, from 0.001 to 4 μM. These cells were initially purchased from ATCC and were gifted by Dr. Arun Rishi (Wayne State University, Detroit, MI, USA) after developing ERL resistance [ 12 ].…”

“…As other suitable drug targets could be combined with TKIs, such as growth factor ligands [ 6 ], apoptotic signaling [ 7 ], inflammation, and angiogenesis [ 8 ], we predicted that methyl 2-cyano-3,11-dioxo-18beta-olean-1,12-dien-30-oate (CDODA-Me) would be an ideal adjunct chemotherapy drug to treat ERL-resistant cell lines owing to its diverse properties. CDODA-Me, a glycyrrhetinic acid derivative, has been shown to decrease the expression of specific proteins [ [9] , [10] , [11] ]; combined with ERL, it causes a synergistic reduction in cell viability [ 12 ]. In the present study, we evaluated the biological changes in ERL-resistant HCC827R cells when compared with HCC827 controls after treatment with ERL, CDODA-Me, and a combination of both drugs.…”

Improving Outcomes of Tyrosine Kinase Inhibitors in Hepatocellular Carcinoma: New Data and Ongoing Trials

“…The newly developed techniques utilizing nanocarriers showed a higher bioavailability and reduction in the off-target tissues or organs. Noticeably, the bioavailability of nanocarrier involving erlotinib was almost 7 times greater than by orally taking (64).…”