Triterpenoids from Momordica balsamina with a Collateral Sensitivity Effect for Tackling Multidrug Resistance in Cancer Cells

Abstract

The collateral sensitivity effect is among the most promising strategies for overcoming multidrug resistance in cancer. In this work, 28 cucurbitane-type triterpenoids (1: -28: ), previously isolated from the African medicinal plant and its derivatives, were evaluated for their collateral sensitivity effect on three different human cancer entities, gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29), each with two different multidrug-resistant variants. One was selected for its resistance to daunorubicin (EPG85-257RDB, EPP85-181RDB, HT-29RDB) and the other was selected for its resistance to mitoxantrone (EPG85-257RNOV, EPP85-181RNOV, HT-29RNOV). On gastric cell lines, the best results were obtained for compounds 3: and 10: , which exhibited a collateral sensitivity effect together with high antiproliferative activity. In turn, on colon cancer cell lines, the best multidrug resistance-selective antiproliferative effects were observed for derivatives 11, 13: , and 15: , which showed collateral sensitivity effects against both resistant variants. Compounds 11: and 3: were also the most selective against the multidrug resistance pancreatic cells lines. Some compounds, such 6, 10, 11: and 15: , were previously found to be strong P-glycoprotein modulators, thus highlighting their potential as promising leads for overcoming multidrug resistance in cancer cells.

Enantioselective Synthesis, DFT Calculations, and Preliminary Antineoplastic Activity of Dibenzo 1-Azaspiro[4.5]decanes on Drug-Resistant Leukemias

“…43 Figure 5 shows that compounds (S)-and (R)-8g, (S)-8h and (R)-8j induced collateral sensitivity on FEPS, since they presented RR ≤ 0.5. 44 Of note, for the standard drugs VCR and DNR this ratio was higher than 2.0, indicative of drug resistance. eV; and fragment ions in m/z with relative intensities (%) in parentheses.…”

“…RR of (R)-8i: IC 50 FEPS / IC 50 K562 = 154.83/200 = 0.77). If RR ≤ 0.5, the compound exerted collateral sensitivity 44 , and cells were considered resistant when RR ≥ 2.0.…”

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

“…Concerning cancer, since the beginning of chemotherapy in the 1940s to date, about 75% of anticancer drugs approved world-wide are natural products or their synthetic derivatives (Newman and Cragg, 2012). In an effort to find out anticancer compounds from plants, for targeting MDR cancer cells, our group has been given particular attention on the development of MDR reversal compounds (Reis et al, 2015;Paterna et al, 2016;Ramalhete et al, 2016;Reis et al, 2016;Reis et al, 2017;Ferreira et al, 2018a;Ferreira et al, 2018b;Paterna et al, 2018;Ramalhete et al, 2018). Duo to the high and unusual chemical diversity of their metabolites, many of which coupled with strong biological properties, we have given particular attention to Euphorbia species (Euphorbiaceae), which are well known since ancient times for their use in folk medicine worldwide, namely, to cure cancer, tumors, and warts (Hartwell, 1969;Ernst et al, 2015).…”

Assessment of Thiosemicarbazone‐Containing Compounds as Potential Antileukemia Agents against P‐gp Overexpressing Drug Resistant K562/A02 Cells

“…Moreover, we also examined their inhibitory effect on the proliferation of parental sensitive leukemic K562 cells to investigate the ability of the target compounds to induce collateral sensitivity (CS) against P‐gp. According to literature methods, [17,18] CS can be quantitatively assessed by calculating the relative resistance (RR) index, which means the ration of IC 50 values of a compound against resistant and corresponding parental sensitive cells.…”