Reversal of P-glycoprotein-mediated multidrug resistance of cancer cells by five schizandrins isolated from the Chinese herb Fructus Schizandrae. Cancer Chemother Pharmacol

Division of Oncology, Department of Internal Medicine, Stanford University, Stanford, CA 94301, USA.
Cancer Chemotherapy and Pharmacology (Impact Factor: 2.77). 03/2008; 62(6):1015-26. DOI: 10.1007/s00280-008-0691-0
Source: PubMed


Fructus Schizandrae (FS) is commonly used as a tonic in traditional Chinese medicine. Recently, FS was found to significantly improve liver dysfunction in chronic hepatitis patients. The present study was to assess the reversal effect of five schizandrins and crude extract from FS (named LCC) on multidrug resistance (MDR) of cancer cells, both in vitro and in vivo. Chemically, the five schizandins are derivatives of dibenzo-(a, c)-cyclooctene lignan with distinct structures differing from any known MDR reversal agents.
A panel of sensitive and resistant cancer cell lines were treated with various concentrations of LCC and schizandrins. Drug sensitivity, accumulation of Doxorubicin (Dox), expression of P-glycoprotein and protein kinase C (PKC), and apoptosis were determined in vitro. The in vivo effect was tested in nude mice grafted with sensitive and resistant human epidermal cancer cell line to vincristine (VCR) (KB, KBv200).
The tested five compounds at 25 muM showed various levels of MDR reversal activity, of which, schizandrin A (Sin A) was the most potent one. Sin A reversed VCR resistance in KBv200 cells, MCF-7/Dox cells and Bel7402 cells by 309-, 38-, and 84-folds, respectively. Also, Sin A reversed the resistance of Dox in the above cancer cell lines. LCC at 25 mug/ml reversed VCR resistance by 619-folds in KBv200, 181-folds in MCF-7/Dox cell line, and 1,563-folds in innate resistance of human hepatic cellular carcinoma Bel7402 cells to VCR. Furthermore, LCC and its active component Sin A potently reversed the cross-resistance to paclitaxel in those cell lines. Both Sin A and LCC markedly increased intracellular Dox accumulation and enhanced apoptosis, down-regulated Pgp protein and mRNA and total PKC expression in MDR cells. Coadministration of LCC (p.o.) significantly potentiated the inhibitory effect of VCR (i.p.) on tumor growth in nude mice bearing KBv200 xenograft.
The LCC and its active component Sin A have remarkable reversal effect on MDR in cancer cells by inhibition of both the function and expression of Pgp and total PKC.

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    • "The concentration of vincristine was chosen according to the previous study (Huang et al., 2008). Body weight, tumor dimensions, feeding behavior and locomotor activity of "
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    ABSTRACT: Background and purpose: The transporter, multidrug resistance protein 1 (MRP1, ABCC1), plays a critical role in the development of multidrug resistance (MDR). Ibrutinib is an inhibitor of Bruton's tyrosine kinase. Here we investigated the reversal effect of ibrutinib on MRP1-mediated MDR. Experimental approach: Cytotoxicity was determined by MTT assay. The expression of protein was detected by Western blot. RT-PCR and Q-PCR were performed to detect the expression of MRP1 mRNA. The intracellular accumulation and efflux of substrates for MRP1 were measured by scintillation counter and flow cytometry. HEK293/MRP1 cell xenografts in nude mice were established to study the effects of ibrutinib in vivo. Key results: Ibrutinib significantly enhanced the cytotoxicity of MRP1 substrates in HEK293/MRP1 and HL60/Adr cells overexpressing MRP1. Furthermore, ibrutinib increased the accumulation of substrates in these MRP1-overexpressing cells by inhibiting the drug efflux function of MRP1. However, mRNA and protein expression of MRP1 remained unaltered after treatment with ibrutinib in MRP1-overexpressing cells. In vivo, ibrutinib enhanced the efficacy of vincristine to inhibit the growth of HEK293/MRP1 tumour xenografts in nude mice. Importantly, ibrutinib also enhances the cytotoxicity of vincristine in primary cultures of leukaemia blasts, derived from patients. Conclusions and implications: Our results indicated that ibrutinib significantly increased the efficacy of the chemotherapeutic agents which were MRP1 substrates, in MRP1-overexpressing cells, in vitro, in vivo and ex vivo. These findings will lead to further studies on the effects of a combination of ibrutinib with chemotherapeutic agents in cancer patients overexpressing MRP1.
    British Journal of Pharmacology 08/2014; 171(24). DOI:10.1111/bph.12889 · 4.84 Impact Factor
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    • "In the past several years, Sch B has been revealed to possess multiple functions against cancer. We and others previously reported that Sch B was a dual inhibitor of P-glycoprotein and multidrug resistance protein 1 (MRP1) [10], [11], [12], [13], [14], [15]. Sch B could also enhance doxorubicin-induced apoptosis in cancer cells, through activation of mitochondrial apoptotic pathway, without obvious enhanced toxicities toward normal cells [16], mitigate doxorubicin-induced acute and chronic cardiotoxicity [17], [18], attenuate cisplatin-induced oxidative stress, genotoxicity and neurotoxicity [19], and inhibit ATR protein kinase activity in response to DNA damage [20]. "
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    ABSTRACT: Metastasis is the major cause of cancer related death and targeting the process of metastasis has been proposed as a strategy to combat cancer. Therefore, to develop candidate drugs that target the process of metastasis is very important. In the preliminary studies, we found that schisandrin B (Sch B), a naturally-occurring dibenzocyclooctadiene lignan with very low toxicity, could suppress cancer metastasis. BALB/c mice were inoculated subcutaneously or injected via tail vein with murine breast cancer 4T1 cells. Mice were divided into Sch B-treated and control groups. The primary tumor growth, local invasion, lung and bone metastasis, and survival time were monitored. Tumor biopsies were examined immuno- and histo-pathologically. The inhibitory activity of Sch B on TGF-β induced epithelial-mesenchymal transition (EMT) of 4T1 and primary human breast cancer cells was assayed. Sch B significantly suppressed the spontaneous lung and bone metastasis of 4T1 cells inoculated s.c. without significant effect on primary tumor growth and significantly extended the survival time of these mice. Sch B did not inhibit lung metastasis of 4T1 cells that were injected via tail vein. Delayed start of treatment with Sch B in mice with pre-existing tumors did not reduce lung metastasis. These results suggested that Sch B acted at the step of local invasion. Histopathological evidences demonstrated that the primary tumors in Sch B group were significantly less locally invasive than control tumors. In vitro assays demonstrated that Sch B could inhibit TGF-β induced EMT of 4T1 cells and of primary human breast cancer cells. Sch B significantly suppresses the lung and bone metastasis of 4T1 cells via inhibiting EMT, suggesting its potential application in targeting the process of cancer metastasis.
    PLoS ONE 07/2012; 7(7):e40480. DOI:10.1371/journal.pone.0040480 · 3.23 Impact Factor
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    • "This antimetastatic effect was conceivably resulted from killing metastatic cells at solitary cell stage (starting from metastatic cells separated from mother body to before forming a mass), similar to Sch B effect on Dox in vitro system where cancer cells were ‘solitary’ rather than tissue-like mass (tumor). Up to date, all the in vitro and in vivo studies without exception demonstrated that Sch B enhanced Dox anticancer activities [13], [16], [17], [18], [19], [20], [22], [34], [35], and there has been no single experiment in vitro and in vivo that ever demonstrated the adverse effect of Sch B on Dox anticancer activities (or any other tested anticancer agents, including anthracyclines, vinca alkaloids, taxanes, epipodophyllotoxins, antimetabolites, DNA topoisomerase inhibitors, tyrosine kinase inhibitors, among others) for the last 7 years of our continuous studies on this compound. "
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    ABSTRACT: To mitigate the cardiotoxicity of anthracycline antibiotics without compromising their anticancer activities is still an issue to be solved. We previously demonstrated that schisandrin B (Sch B) could protect against doxorubicin (Dox)-induced acute cardiotoxicity via enhancing cardiomyocytic glutathione redox cycling that could attenuate oxidative stress generated from Dox. In this study, we attempted to prove if Sch B could also protect against Dox-induced chronic cardiotoxicity, a more clinically relevant issue, without compromising its anticancer activity. Rat was given intragastrically either vehicle or Sch B (50 mg/kg) two hours prior to i.p. Dox (2.5 mg/kg) weekly over a 5-week period with a cumulative dose of Dox 12.5 mg/kg. At the 6th and 12th week after last dosing, rats were subjected to cardiac function measurement, and left ventricles were processed for histological and ultrastructural examination. Dox anticancer activity enhanced by Sch B was evaluated by growth inhibition of 4T1, a breast cancer cell line, and S180, a sarcoma cell line, in vitro and in vivo. Pretreatment with Sch B significantly attenuated Dox-induced loss of cardiac function and damage of cardiomyocytic structure. Sch B substantially enhanced Dox cytotoxicities toward S180 in vitro and in vivo in mice, and increased Dox cytotoxcity against 4T1 in vitro. Although we did not observe this enhancement against the implanted 4T1 primary tumor, the spontaneous metastasis to lung was significantly reduced in combined treatment group than Dox alone group. Sch B is capable of protecting Dox-induced chronic cardiotoxicity and enhancing its anticancer activity. To the best of our knowledge, Sch B is the only molecule ever proved to function as a cardioprotective agent as well as a chemotherapeutic sensitizer, which is potentially applicable for cancer treatment.
    PLoS ONE 12/2011; 6(12):e28335. DOI:10.1371/journal.pone.0028335 · 3.23 Impact Factor
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