It has been reported that gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has the ability to modulate the function of certain ATP-binding cassette (ABC) transporters and to reverse ABC subfamily B member 1 (ABCB1; P-glycoprotein)-and ABC subfamily G member 2 (ABCG2; breast cancer resistance protein/mitoxantrone resistance protein)-mediated multidrug resistance (MDR) in cancer cells. However, it is unknown whether other EGFR TKIs have effects similar to that of gefitinib. In the present study, we have investigated the interaction of another EGFR TKI, erlotinib, with selected ABC drug transporters. Our findings show that erlotinib significantly potentiated the sensitivity of established ABCB1 or ABCG2 substrates and increased the accumulation of paclitaxel or mitoxantrone in ABCB1-or ABCG2-overexpressing cells. Furthermore, erlotinib did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in all cells and was unable to reverse MRP1-mediated MDR and had no effect on the parental cells. However, erlotinib remarkably inhibited the transport of E 2 17BG and methotrexate by ABCG2. In addition, the results of ATPase assays show that erlotinib stimulated the ATPase activity of both ABCB1 and ABCG2. Interestingly, erlotinib slightly inhibited the photolabeling of ABCB1 with [125 I] iodoarylazidoprazosin (IAAP) at high concentration, but it did not inhibit the photolabeling of ABCG2 with IAAP. Overall, we conclude that erlotinib reverses ABCB1-and ABCG2-mediated MDR in cancer cells through direct inhibition of the drug efflux function of ABCB1 and ABCG2. These findings may be useful for cancer combinational therapy with erlotinib in the clinic. [Cancer Res 2007;67(22):11012-20]

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...

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Two new 3,4-epoxy group-containing abietane diterpenoids (1 and 2), together with five known diterpenoids (3−7), were isolated from Ajuga decumbens. Their structures were elucidated by spectroscopic data analysis, NMR calculations, and X-ray diffraction experiments. The structures of two known abietane diterpenoids were revised based on NMR calculations and X-ray diffraction data. Notably, compound 4 specifically inhibited RSL3-induced ferroptosis with an EC 50 of 56 nM by antioxidation. Moreover, 4 significantly decreased RSL3-induced lipid and cytosolic ROS accumulation and ferroptosis marker gene PTGS2 mRNA expression. This work reports the most potent natural inhibitor against ferroptosis found so far.

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