• Asian Pacific Journal of Cancer Prevention
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• v.16 no.16
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• pp.6831-6839
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• 2015

Multidrug resistance is a principal mechanism by which tumors become resistant to structurally and functionally unrelated anticancer drugs. Resistance to chemotherapy has been correlated with overexpression of p-glycoprotein (p-gp), a member of the ATP-binding cassette (ABC) superfamily of membrane transporters. P-gp mediates resistance to a broad-spectrum of anticancer drugs including doxorubicin, taxol, and vinca alkaloids by actively expelling the drugs from cells. Use of specific inhibitors/blocker of p-gp in combination with clinically important anticancer drugs has emerged as a new paradigm for overcoming multidrug resistance. The aim of this paper is to review p-gp regulation by dietary nutraceuticals and to correlate this dietary nutraceutical induced-modulation of p-gp with activity of anticancer drugs.

• Journal of Microbiology and Biotechnology
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• v.29 no.4
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• pp.571-576
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• 2019

Microenvironmental stress, which is naturally observed in solid tumors, has been implicated in anticancer drug resistance. This tumor-specific stress causes the degradation of topoisomerase $II{\alpha}$, rendering cells resistant to topoisomerase $II{\alpha}$-targeted anticancer agents. In addition, microenvironmental stress can induce the overexpression of 78kDa glucose regulated protein (GRP78), which can subsequently block the activation of apoptosis induced by treatment with anticancer agents. Therefore, inhibition of topoisomerase $II{\alpha}$ degradation and reduction in GRP78 expression may be effective strategies for inhibiting anticancer drug resistance. In this study, we investigated the active compound arctigenin, which inhibited microenvironmental stress-induced etoposide resistance in HT-29 cells. Arctigenin was also highly toxic to etoposide-resistant HT-29 cells, with an $IC_{50}$ value of $10{\mu}M$ for colony formation. We further showed that arctigenin inhibited the degradation of topoisomerase $II{\alpha}$ and reduced the expression of GRP78. Thus, these results suggest that arctigenin is a novel therapeutic agent that inhibits resistance to etoposide associated with microenvironmental stress conditions.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2000.04a
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• pp.8-9
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• 2000

Despite the advances made in the past few decades in cancer chemotherapy, many conventional anticancer drugs display relatively poor selectivity for cancer cells. The nonselectivity of anticancer drugs and the development of anticancer drug resistance have been recognized as serious limitations in their clinical usefulness. Therefore, a major challenge in cancer chemotherapy is the development of new anticancer agents with improved selectivity for tumor cells as well as the prevention of the host cell resistance, both of which result in the improvement of therapeutic effect against cancer cells. Cyclophosphamide (CP), a widely used anticancer agent, is a prodrug that is activated by hepatic microsomal mixed-function oxidase (MFO) catalyzed C$_4$- hydroxylation. The resulting 4-hydroxycyclophosphamide (4-OH-CP) is converted to the ring-opened tautomer to aldophosphamide (Aldo) which subsequently undergoes a base- catalyzed ${\beta}$-elimination to generate cytotoxic phosphoramide mustard (PDA) and acrolein. The cytotoxic activity of CP is attributed to the aziridinium ion species derived from PDA that cross-links interstrand DNA.

• Toxicological Research
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• v.33 no.1
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• pp.1-5
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• 2017

Nuclear factor E2-related factor 2 (Nrf2), a transcription factor, controls the expression of genes encoding cytoprotective proteins, including antioxidant enzymes that combat oxidative and electrophilic stress to maintain redox homeostasis. However, recent studies demonstrated that, in cancer, aberrant activation of Nrf2 by epigenetic alterations promotes high expression of cytoprotective proteins, which can decrease the efficacy of anticancer drugs used for chemotherapy. In this review, we summarize recent findings regarding the relationship between oxidative stress, Nrf2, epigenetic modification, and anticancer drug resistance, which should aid in development of new strategies to improve chemotherapeutic efficacy.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.167.2-168
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• 2003

Anticancer drug resistance occasionally occurs in malignant hematologic diseases such as acute myelocytic leukemia (AML) treated with chemotherapy and is a major problem to complete remission. Malignant cells primarily induce intrinsic resistance to treatment of anticancer drug, but gradually obtain acquired resistance to cytotoxic activities of chemotherapy. In this study, we monitored the expression profiles of doxorubicin resistance-related genes in AML-2/DX100, a doxorubicin-resistant human acute myelocytic leukemia cell line. (omitted)

• Proceedings of the Korean Society of Applied Pharmacology
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• 2002.07a
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• pp.97-102
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• 2002

Life Science Research Center of SK Chemicals has developed a 3rd-generation anticancer platinum drug for the first time in the nation′s 100-year-old pharmaceutical industry. The Korea Food and Drug Administration (KFDA) approved the sale of "Sunpla" (code name SKI 2053R, general name : Heptaplatin) on July 14, 1999 for the treatment of advance, metastatic gastric cancer. Cisplatin, the 1 st-generation anticancer drug, which was developed by Bristol-Myers of the United States in 1976, is one of the most potent anticancer drugs and is a major component of combination chemotherapy for a variety of human cancers. However its clinical usefulness has frequently been limited not only by undesirable side effects such as severe renal toxicity, nausea, vomiting, ototoxicity, and neurotoxicity but also by the development of resistance. Carboplatin, the 2nd-generation anticancer platinum drug, which was also developed by Bristol-Myers in 1986, has modified the problems of the renal and gastrointestinal toxicities of cisplatin. Carboplatin, however, has no enhanced therapeutic efficacy over cisplatin and does not possess the property to overcome cross-resistance to cisplatin.

• Journal of Microbiology and Biotechnology
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• v.17 no.11
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• pp.1856-1861
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• 2007

Physiological cell conditions such as glucose deprivation and hypoxia play roles in the development of drug resistance in solid tumors. These tumor-specific conditions cause decreased expression of DNA topoisomerase $II{\alpha}$, rendering cells resistant to topo II target drugs such as etoposide. Thus, targeting tumor-specific conditions such as a low glucose environment may be a novel strategy in the development of anticancer drugs. On this basis, we established a novel screening program for anticancer agents with preferential cytotoxic activity in cancer cells under glucose-deprived conditions. We recently isolated an active compound, AA-98, from Streptomyces sp. AA030098 that can prevent stress-induced etoposide resistance in vitro. Furthermore, LC-MS and various NMR spectroscopic methods identified AA-98 as mithramycin, which belongs to the aureolic acid group of antitumor compounds. We found that mithramycin prevents the etoposide resistance that is induced by glucose deprivation. The etoposide-chemosensitive action of mithramycin was just dependent on strict low glucose conditions, and resulted in the selective cell death of etoposide-resistant HT-29 human colon cancer cells.

• Journal of Pharmaceutical Investigation
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• v.41 no.6
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• pp.381-386
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• 2011

Multi-drug resistance (MDR) has been known as a major hurdle in cancer chemotherapy. One of the most clinically significant causes of MDR was the efflux of anticancer agents mediated by p-glycoprotein (p-gp) over-expressed in MDR cancer cells. To overcome MDR, there have been several strategies such as co-administration with p-gp inhibitors and encapsulation of anticancer drugs into drug delivery systems. In the present study, curcumin was evaluated for its potential as p-gp inhibitor and MDR reversal activity when combined with paclitaxel incorporated into lipid nanoparticles (PTX/LN). Western blot assay showed curcumin did not modulate the level of p-gp expression in MCF-7/ADR which is a MDR variant of human breast cancer cell line, MCF-7, and over-expresses p-gp. However, curcumin inhibited p-gp-mediated efflux of calcein in a dose-dependent manner even though it showed lower activity compared to verapamil, a well-known p-gp inhibitor. Incorporation of paclitaxel into lipid nanoparticles partially recovered the anticancer activity of paclitaxel in MCF-7/ADR. The combined use of curcumin and PTX/LN exhibited further full reversal of MDR, suggesting susceptibility of PTX/LN to the efflux system. In conclusion, combined approach of using p-gp inhibitors and incorporation of the anticancer agents into nano-delivery systems would be an efficient strategy to overcome MDR.

• Journal of Microbiology and Biotechnology
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• v.27 no.8
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• pp.1367-1378
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• 2017

Epigenetic alterations such as DNA methylation, histone acetylation, and chromatin remodeling can control gene expression by regulating gene transcription. DNA methylation is one of the frequent epigenetic events that play important roles in cancer development. Cancer cells can gain significant resistance to anticancer drugs and escape programmed cell death through major epigenetic changes, including DNA methylation. To date, several research groups have identified instances of both (i) hypermethylation of tumor suppressor genes, and (ii) global hypomethylation of oncogenes. These changes in DNA methylation status could be used as biomarkers for the diagnosis and prognosis of cancer patients undergoing chemotherapies or other clinical therapies. Herein, we describe genes for which methylation is dependent upon anticancer drug resistance in patients with gastric cancer; we then suggest a significant epigenetic target to focus on for overcoming anticancer drug resistance.

• Archives of Pharmacal Research
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• v.19 no.5
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• pp.342-347
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• 1996

Doxorubicin, one of the clinically most useful anticancer agents, is used alone or in combination with other drugs against a wide variety of tumors, recently. But cancer cells developed resistance to this agent in many ways. This resistance is an important limiting factor of doxorubicin for anticancer drug. We newly established doxorubicin-resistant HCT15/CL02 subline from parental HCT15 human adenocarcinoma colon cancer cells. HCT15/CL02 revealed resistance to doxorubicin about 85-fold of its parental cells, and it also revealed cross-resistance to actinomycin D, etoposide and vinblastine but not to displatin and tamoxifen. And verapamil, a reversal agent of multidrug-resistance (MDR) by P-glycoprotein, elevated the cytotoxicity of doxorubicin against both HCT15 and GCT15/CL02 cells. But the relative resistant rate was not reduced. Verapamil had no effects on the tosicity of cisplatin to the both cell lines. These results indicate that HCT15/CL02 cells have some functionally complex mechanisms for MDR.