Icariin Enhances Cytotoxicity of Doxorubicin in Human Multidrug-Resistant Osteosarcoma Cells by Inhibition of ABCB1 and Down-Regulation of the PI3K/Akt Pathway

Abstract

Multidrug resistance is one of the major causes limiting the efficacy of chemotherapeutic agents used to control osteosarcoma. Multidrug resistance protein 1 (MDR1 or ABCB1) was considered to play a critical role in multidrug resistance. Agents from traditional Chinese medicines (TCMs) have great potential to prevent the onset or delay the progression of the carcinogenic process, and also to enhance the efficacy of mainstream antitumor agents. Herein, we investigated the effect and mechanism of icariin in the human osteosarcoma doxorubicin ( Key words osteosarcoma; icariin; multidrug resistance (MDR); phosphatidyl inositol 3-kinase (PI3K)/Akt pathwayChemotherapy is regarded as an important line of defense against osteosarcoma which is the most common primary mesenchymal malignant tumor of bone tissue in human, especially in children and adolescents. However, on account of drug resistance especially multidrug resistance (MDR), only a limited proportion of cancer patients respond favorably to commonly used chemotherapeutic drugs.1) With respect to the mechanisms of multidrug resistance, ATP-binding cassette transporters, such as ABCB1 (MDR1, P-glycoprotein (P-gp)), ABCC1/multidrug resistance-associated protein 1 (MRP1) and ABCG2/breast cancer resistance protein (BCRP), mediate energy-dependent drug efflux and play a main role in chemoresistance.2,3) And central to the mechanism is the overexpression of MDR1, which extrudes (certainly but not only) Vinca alkaloids, anthracyclines, epipodophyllotoxins, and taxanes out of cancer cells. 4)Inhibiting drug transporter and modulating MDR are one of the most important strategies in the field of cancer chemotherapy. First-generation inhibitors of P-gp such as verapamil (VPL) and cyclosporine were combined with a range of chemotherapy regimens for many cancers, but the results were not convincing. The second-generation inhibitors of P-gp such as PSC 833 and VX-710 were attempted in subsequent clinical trials, but the results of these trialswere largely negative, failing in some cases because of pharmacokinetic interaction between the chemotherapeutic agents and the P-gp inhibitors.5) The third-generation inhibitors of P-gp and MRP1 such as tariquidar (XR9576), Zosuquiar (LY335979), Laniquidar (R102933), and may be more effective in certain patients with MDR. [6][7][8][9] However, none of them was approved for clinical use due to their unwanted side effects.Therefore, the screening of more potent chemosensitizers with desirable pharmacology is of paramount clinical importance.Agents derived from plant origin are being increasingly utilized in drug discovery and drug development programs. 10,11) Identification of natural compounds capable of circumventing MDR with minimal adverse side effects is an attractive goal. For example, flavonoids are a group of compounds which have been extensively studied as chemosensitizers in a number of cancer cell lines. 12) Icariin (Fig. 1), one of the most abundant flavonoids in Herba Epimedii, has lots of pharmacological and biological acti...

Interference of P-REX2a may inhibit proliferation and reverse the resistance of SGC7901 cells to doxorubicin

“…Doxorubicin is one of the classical drugs with reported cases of resistance against it. Furthermore, the PI3K/Akt signaling pathway has been implicated in the majority of cases of resistance (17)(18)(19)(20).…”

Timosaponin A-III reverses multi-drug resistance in human chronic myelogenous leukemia K562/ADM cells via downregulation of MDR1 and MRP1 expression by inhibiting PI3K/Akt signaling pathway

“…The phosphoinositide 3-kinase/serine-threonine kinase (PI3K/Akt) signaling pathway is a well-known fundamental intracellular signaling transduction pathway involved in multiple biological processes both in normal and cancer cells, including gene transcription and translation, cell growth, proliferation and survival, cell metabolism, cell cycle progression, apoptosis and autophagy (8)(9)(10). Besides, there is an increasing amount of preclinical data supporting that the PI3K/Akt signaling pathway is also involved in the drug resistance of different types of human malignant cells, including CML (2,4,5,(12)(13)(14)(15). A previous study demonstrated that the resistant CML cell line K562/ADM presented higher PI3K/ Akt activity than the sensitive one and was in accordance with the MDR phenotype (2).…”

Icariin Prevents H2O2‐Induced Apoptosis via the PI3K/Akt Pathway in Rat Nucleus Pulposus Intervertebral Disc Cells

“…However, there are few reports on the effect of traditional Chinese medicines, such as icariin, on NP and annulus fibrosus cells, although, as an old Chinese traditional medicine, icariin has been reported to benefit osteogenesis in vivo [14], accelerate the differentiation of osteoblast and mesenchymal stem cells [15], and protect neurocytes [16]. Additional effects are described in numerous review articles [9, 15, 17–24]. …”

“…Qianggu Capsule, which contains icariin, is used to treat postmenopausal and posttraumatic osteoporosis. An increasing number of articles have reported that icariin possesses multiple biological activities, such as improvement of drug resistance to chemotherapy [9], tumor-suppression, and antioxidation. Additionally, we find that icariin has an initiative pathophysiological effect on the reversal of IVD degeneration.…”