Epoxylathyrane Derivatives as MDR-Selective Compounds for Disabling Multidrug Resistance in Cancer

Abstract

Background: Multidrug resistance (MDR) has been regarded as one of the major hurdles for the successful outcome of cancer chemotherapy. The collateral sensitivity (CS) effect is one the most auspicious anti-MDR strategies. Epoxylathyrane derivatives 1-16 were obtained by derivatization of the macrocyclic diterpene epoxyboetirane A (17), a lathyranetype macrocyclic diterpene isolated from Euphorbia boetica. Some of these compounds were found to strongly modulate P-glycoprotein (P-gp/ABCB1) efflux.Purpose: The main goal was to develop lathyrane-type macrocyclic diterpenes with improved MDR-modifying activity, by targeting more than one anti-MDR mechanism.Study design/methods: In this study, the potential CS effect of compounds 1-16 was evaluated against gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29) human cancer cells and their drug-resistant counterparts, respectively selected against mitoxantrone (EPG85-257RNOV; EPP85-181RNOV; HT-RNOV) or daunorubicin (EPG85-257RDB; EPP85-181RDB; HT-RDB). The most promising compounds (8, 15, and 16) were investigated as apoptosis inducers, using the assays annexin V/PI and active caspase-3. Results:The compounds were more effective against the resistant gastric cell lines, being the CS effect more significant in EPG85-257RDB cells. Taking together the IC 50 values and the CS effect, compounds 8, 15, and 16 exhibited the best results. Epoxyboetirane P (8), with the strongest MDR-selective antiproliferative activity against gastric carcinoma EPG85-257RDB cells (IC 50 of 0.72 µM), being 10-fold more active against this resistant subline than in sensitive gastric carcinoma cells. The CS effect elicited by compounds 15 and 16 appeared to be by inducing apoptosis via caspase-3 activation. Structure-activity relationships of the compounds were additionally obtained through regression models to clarify the structural determinants associated to the CS effect.Conclusions: This study reinforces the importance of lathyrane-type diterpenes as lead molecules for the research of MDR-modifying agents.

Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

“…Chemical derivatization has been widely used as a strategy for improving not only the biological activity, but also the pharmacokinetic properties of these NPs. Using this approach, terpenes have been used as attractive starting points to obtain new compounds with potential to overcome the multidrug resistance in cancer [ 125 , 126 , 127 ].…”

Zoopharmacology: A Way to Discover New Cancer Treatments

“…Many mechanisms have been proposed for CSC resistance, such as drug efflux through ABC transporters, microenvironment modulation, epigenome, exomes, overactivation of the DNA damage response, apoptosis evasion, increased unfolded protein response (transforming the cells particularly susceptible to endoplasmic reticulum stress and mitochondrial damage), autophagy deregulation, metabolic alterations, prosurvival pathways activation, and/or cell cycle promotion [ 3 ]. These mechanisms are still not completely understood and could occur simultaneously [ 6 ]. Nonetheless, targeted therapy toward these specific CSC mechanisms is only partially effective to prevent or abolish resistance, suggesting underlying additional causes for CSC resilience [ 3 ].…”

“…To combat drug resistance, there are two main strategies: (1) Drugs with novel modes of action to bypass resistance to established drugs or (2) inhibitors of resistance mechanisms for resensitization of tumor cells [ 8 ]. The most general approach has been the development of P-glycoprotein (P-gp) inhibitors to co-administer with anticancer drugs [ 6 ]. This consists of the pharmacological blockage of drug transporters such as P-gp (a type of ABC transporter) [ 8 ], that can lower intracellular drug concentration by expelling the drug from cancer cells [ 5 ].…”

“…This consists of the pharmacological blockage of drug transporters such as P-gp (a type of ABC transporter) [ 8 ], that can lower intracellular drug concentration by expelling the drug from cancer cells [ 5 ]. However, despite their great in vitro success, there is no P-gp inhibitor currently available for clinical use [ 6 ].…”

“…Although many hypotheses have been proposed, the mechanism of collateral sensitizing compounds remains unclear; nonetheless, they seem to be related to diverse biochemical mechanisms. A recent work assessed the ability of the macrocyclic diterpene plant derivatives as collateral sensitizing compounds in human tumor gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29) cell models (drug-sensitive and drug-resistant sublines) [ 6 ].…”