Ecdysteroids Sensitize MDR and Non-MDR Cancer Cell Lines to Doxorubicin, Paclitaxel, and Vincristine but Tend to Protect Them from Cisplatin

Abstract

Ecdysteroids, analogs of the insect molting hormone, are known for their various mild, nonhormonal bioactivities in mammals. Previously, we reported that less-polar ecdysteroids can modulate the doxorubicin resistance of a multidrug resistant (MDR) mouse lymphoma cell line expressing the human ABCB1 transporter. Here, we describe the ability of 20-hydroxyecdysone (1) and its mono- (2) and diacetonide (3) derivatives to sensitize various MDR and non-MDR cancer cell lines towards doxorubicin, paclitaxel, vincristine, or cisplatin. Drug IC50 values with or without ecdysteroid were determined by MTT assay. Compound 3 significantly sensitized all cell lines to each chemotherapeutic except for cisplatin, whose activity was decreased. In order to overcome solubility and stability issues for the future in vivo administration of compound 3, liposomal formulations were developed. By means of their combination index values obtained via checkerboard microplate method, a formulation showed superior activity to that of compound 3 alone. Because ecdysteroids act also on non-ABCB1 expressing (sensitive) cell lines, our results demonstrate that they do not or not exclusively exert their adjuvant anticancer activity as ABCB1 inhibitors, but other mechanisms must be involved, and they opened the way towards their in vivo bioactivity testing against various cancer xenografts.

Overexpression of suppressor of IKBKE 1 is associated with vincristine resistance in colon cancer cells

“…The resistance mechanism of VCR is complex and involves numerou molecules, such as insulin like growth factor binding protein 7, multidrug resistance protein 1, miRNAs, and long non-coding RNA (11,18-23). A previous study demonstrated that IKBKE 1 in VCR-resistant colon cancer cell lines was significantly increased by >14-fold compared with in non-resistant cells (17). Consistent with this result, the present study identified that IKBKE 1 expression in the VCR-resistant cells was significantly higher than in the non-resistant cells using RT-qPCR and western blotting.…”

“…VCR is widely administered to clinically treat certain cancers, including leukemia and lung cancer; however, tumor cells may develop drug resistance (14)(15)(16)(17). The resistance mechanism of VCR is complex and involves numerou molecules, such as insulin like growth factor binding protein 7, multidrug resistance protein 1, miRNAs, and long non-coding RNA (11,18-23).…”

Stereochemistry and complete 1H and 13C NMR signal assignment of C‐20‐oxime derivatives of posterone 2,3‐acetonide in solution state

“…Less polar derivatives of ecdysteroids, and particularly their acetonides and other dioxolane analogs, were previously shown by our group to exert a strong chemo‐sensitizing activity on cancer cells to common chemotherapeutics, including doxorubicin, vincristine, and paclitaxel . While this sensitizing activity could also be observed on drug‐susceptible cancer cells, a high selectivity was found towards multidrug resistant (MDR) cancer cell lines transfected to overexpress the ABCB1 multidrug transporter .…”

“…Less polar derivatives of ecdysteroids, and particularly their acetonides and other dioxolane analogs, were previously shown by our group to exert a strong chemo‐sensitizing activity on cancer cells to common chemotherapeutics, including doxorubicin, vincristine, and paclitaxel . While this sensitizing activity could also be observed on drug‐susceptible cancer cells, a high selectivity was found towards multidrug resistant (MDR) cancer cell lines transfected to overexpress the ABCB1 multidrug transporter . Interestingly, the chemo‐sensitizing activity was independent of a functional efflux inhibition: even though some of the tested compounds showed a mild to moderate ABCB1 inhibitory activity; structure–activity relationships for efflux inhibition were significantly different to those describing chemo‐sensitizing activity .…”

HPLC analysis and blood-brain penetration of 20-hydroxyecdysone diacetonide

“…Lipophilicity of several ecdysteroids was determined using reversed-phase thin-layer chromatography, giving in the order of decreasing R M values such as cyasterone, 22-deoxy-20-hydroxyecdysone, 2-deoxyecdysone, viticosterone E, makisterone A, 22-deoxy-20-hydroxyecdysone, 20-hydroxyecdysone 22 acetate, rubrosterone, polypodine B, 20-hydroxyecdysone, and integristerone A [9]. Martins et al described that less polar ecdysteroid derivatives, in particularly those with substituted dioxolane rings at positions 2,3 and 20,22 like, for example, diacetonides, can exert a strong chemo-sensitizing activity on various cancer cell lines including drug-sensitive as well as multidrug-resistant ones [10][11][12]. In a most recent study by Müller et al (Eur.…”