Sipholenol A, a marine‐derived sipholane triterpene, potently reverses P‐glycoprotein (ABCB1)‐mediated multidrug resistance in cancer cells

Abstract

Through extensive screening of marine sponge compounds, the authors have found that sipholenol A, a sipholane triterpene isolated from the Red Sea sponge, Callyspongia siphonella, potently reversed multidrug resistance (MDR) in cancer cells that overexpressed P-glycoprotein (P-gp). In experiments, sipholenol A potentiated the cytotoxicity of several P-gp substrate anticancer drugs, including colchicine, vinblastine, and paclitaxel, but not the non-P-gp substrate cisplatin, and significantly reversed the MDR of cancer cells KB-C2 and KB-V1 in a concentration-dependent manner. Furthermore, sipholenol A had no effect on the response to cytotoxic agents in cells lacking P-gp expression or expressing MDR protein 1 or breast cancer resistance protein. O verexpression of P-gp is one of the most common and well-studied causes of MDR in cancer cells. P-gp, a 170-KD transmembrane glycoprotein encoded by the human MDR1 (ABCB1) gene, is a member of the ABC transporters family. It functions as a drug efflux pump that extrudes a wide range of structurally and mechanistically different drugs out of cells. Drugs transported by P-gp include Vinca alkaloids, anthracyclines, epipodophyllotoxins and taxanes, (1) and this process of transport is coupled to the energy provided by ATP hydrolysis via the ATPase domains of P-gp that are stimulated in the presence of transport substrates.(2) Therefore, in theory, inhibition of P-gpmediated drug efflux may re-sensitize MDR cancer cells to treatment with chemotherapeutic agents, and lead to an effective chemotherapy for patients with an MDR tumor. Currently, a few P-gp inhibitors are developed and show potent inhibition of P-gp function to enhance the effect of chemotherapeutic drugs on MDR cancer cells in vitro and in vivo. These compounds include verapamil, quinidine, cyclosporin A, PSC-833 (valspodar),VX-710 (biricodar), (4) R101933 (laniquidar),oc144-093 (ONT-093), (6) LY335979 (zosuquidar),GF-120918 (elacridar),and XR9576 (tariquidar).In clinical trials, the first-generation P-gp inhibitors, including verapamil, quinine and cyclosporin A, failed to show an improvement in therapeutic outcome and toxic side-effects were common.(10) The second-generation inhibitor, PSC-388, albeit tested most frequently in clinical trials, also failed in inducing pharmacokinetic interactions that limited the clearance and metabolism of chemotherapeutic drugs, and this increased plasma concentrations beyond acceptable levels of toxicity. (11) The third-generation inhibitors are currently being studied for their clinical efficacy. Due to the reasons mentioned above, no P-gp inhibitors have been approved for clinical use. Consequently, it is necessary to develop more efficient and non-toxic compounds to reverse MDR in cancer cells. In the course of the authors' search for MDR-reversing agents, several novel P-gp inhibitors and/or strategies have successfully been exploited to target MDR in vitro and/or in vivo, including tetrandrine, (12,13) FG020326 and several of its derivatives, (14,15) ONO-1078,5-O-benz...

Marine Natural Products as Models to Circumvent Multidrug Resistance

“…Compound 1 also inhibited P-gp-mediated drug efflux and did not alter the expression of P-gp after treatment in KB-C2 and KB-V1 cells. This compound stimulated the activity of ATPase, and also inhibited the photo-labeling transporter with [ 125 I]-iodoarylazidoprazosin [44]. From SAR studies (Figure 1), it was demonstrated that substitution of the methyl group on C-15 by carbonyl or alcohol reduced the MDR-inhibitory activity, while changing from a hydroxyl to a ketone function at C-4 also reduced the activity [48].…”

“…This class of triterpenes consists of sipholenol A (1), sipholenone E (2), sipholenol L (3), and siphonellinol D (4), isolated from the Red Sea sponge Callyspongia siphonella [44,45], and semisynthetic derivatives of sipholenol A such as sipholenol A-4-O-acetate (5), sipholenol A-4-O-isonicotinate (6) [39], sipholenol A-4-O-3',4'-dichlorobenzoate (7) [46], sipholenol A 4-O-4'-chlorobenzoate (8), and 19,20-anhydrosipholenol A 4-O-4'-chlorobenzoate (9) [47] that were synthesized using a ligand-based design approach. Natural and semisynthetic siphonane triterpenoids were shown to reverse MDR activities (1-6), and display antimigratory and antiproliferative activities in breast cancer cell lines (7)(8)(9).…”

<i>In vitro</i> Cytotoxic, Antibacterial and Antiviral Activities of Triterpenes from the Red Sea Sponge, <i>Siphonochalina siphonella</i>

“…The NMR data were identical with those of sipholenone (compound 1), except for the absence of the carbonyl carbon which is replaced by oxymethine group at C-4 (δ H 3.81, dd 6.5, 3.5) and δ C (76.8). The MS and NMR spectral data confirmed compound 2 to be sipholenol A [3,6,9,10].…”

“…Several studies have described remarkable anti-proliferative activity of sipholane triterpenoids and some of their semisynthetic derivatives against a number of highly malignant cell lines [9]. Sipholenol A was found to potently reverse P-gp-mediated MDR (permeability glycoprotein-mediated multiple drug resistance) to colchicine, paclitaxel, and vinblastine in the resistant KB-C2 and KB-V1 cells overexpressing P-gp [10]. Biocatalysis of sipholenol A and sipholenone A were useful in getting new similar triterpenes with potent antiproliferative activity [11].…”

Natural Compounds: Molecular Weapons against Leukemia’s

“…Recent findings have shown that these compounds interact with transporter proteins to inhibit drug efflux mediated by MDR1, MRP1 or BCRP. In particular, triterpenoids can act with different mechanisms, including direct interaction with the Pglycoprotein (P-gp) active site, stimulating the activity of the P-gp ATPase [33], or decreasing P-gp expression in a dose-dependent manner [34].…”