Down-regulation of lipids transporter ABCA1 increases the cytotoxicity of Nitidine

Iwasaki, Hiromichi; Okabe, Takafumi; Takara, Kensaku; Yoshida, Yasuhiko; Hanashiro, Kaoru; Oku, Hirosuke

doi:10.1007/s00280-010-1247-7

Cited by 19 publications

(15 citation statements)

References 23 publications

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“…Our previous study demonstrated that NTD efflux is controlled by the activity of the ABCA1 transporter . CPT treatment in the present study significantly increased the expression of ABCC1, ABCC2, ABCC3 (ABCC1–3) and ABCA1 (Fig.…”

Section: Discussionsupporting

confidence: 63%

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Enhanced cytotoxicity of nitidine against camptothecin-resistant A549 cells

Taira

Iwasaki

Inafuku

et al. 2015

Traditional & Kampo Medicine

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Aim: Drug resistance has been a major issue in cancer chemotherapy. It is therefore important to screen more potent natural anti-cancer agents for use against the drug-resistant cancer phenotype. The present study investigated the cytotoxicity of the traditional and natural medicinal agent nitidine (NTD) against the drug-resistant cancer phenotype of A549 human lung adenocarcinoma cells. Methods: The camptothecin (CPT) tolerant phenotype was selected after A549 cells were exposed to CPT for 1 week. The cytotoxicity of NTD in these CPT-resistant cells (CRC) was studied in vitro in relation to its accumulation and expression of the ATP binding cassette (ABC) transporter gene. Results: CRC expressing higher levels of ABCC1, ABCC2, ABCC3, and ABCA1 were more resistant to CPT compared with normal A549 cells. CRC were, however, more susceptible to NTD compared with normal A549 cells with preferential accumulation of NTD. A statistically significant difference in protein level between normal A549 and CRC was noted only for ABCC1 and ABCC2. Furthermore, gene expression of ABCC2 and ABCC3 had a positive correlation with NTD accumulation, and negative correlation with the effective dose that inhibited 50% of cell growth (D 50 ) of this agent in nine cancer cell panels. Conclusion: CRC were found to be more susceptible to NTD compared with the normal phenotype. The cytotoxicity of NTD was associated with its accumulation and the expression of ABCC2, suggesting the involvement of this transporter in the selective incorporation of NTD into cancer cells, resulting in enhanced cytotoxicity.

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Section: Discussionsupporting

confidence: 63%

“…NTD accumulation in A549 cancer cells was higher than that in normal WI‐38 cells despite the high expression of ABCC2 or ABCC3 , suggesting that these ABC transporters are not involved in the efflux of NTD. NTD, as well as CPT, is assumed to enter the cells by passive diffusion.…”

Section: Discussionmentioning

confidence: 92%

Enhanced cytotoxicity of nitidine against camptothecin-resistant A549 cells

Taira

Iwasaki

Inafuku

et al. 2015

Traditional & Kampo Medicine

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“…Our previous study identified ATP-binding cassette subfamily A member 1 (ABCA1) as an NTD transporter. ABCA1 is known as a cholesterol transporter [31]. These results suggested that the unique tumor cell selectivity of NTD shown in the present experiment might be supported by various features, such as the efflux activity of ABCB1, ABCA1, and MMP.…”

Section: Discussionsupporting

confidence: 52%

Tumor-Selective Cytotoxicity of Nitidine Results from Its Rapid Accumulation into Mitochondria

Iwasaki

Inafuku

Taira

et al. 2017

BioMed Research International

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We identified a nitidine- (NTD-) accumulating organelle and evaluated the net cytotoxicity of accumulated NTD. To evaluate tumor cell selectivity of the drug, we evaluated its selective cytotoxicity against 39 human cancer cell lines (JFCR39 panel), and the profile was compared with those of known anticancer drugs. Organelle specificity of NTD was visualized using organelle-targeted fluorescent proteins. Real-time analysis of cell growth, proliferation, and cytotoxicity was performed using the xCELLigence system. Selectivity of NTD in the JFCR39 panel was evaluated. Mitochondria-specific accumulation of NTD was observed. Real-time cytotoxicity analysis suggested that the mechanism of NTD-induced cell death is independent of the cell cycle. Short-term treatment indicated that this cytotoxicity only resulted from the accumulation of NTD into the mitochondria. The results from the JFCR39 panel indicated that NTD-mediated cytotoxicity resulted from unique mechanisms compared with those of other known anticancer drugs. These results suggested that the cytotoxicity of NTD is only induced by its accumulation in mitochondria. The drug triggered mitochondrial dysfunction in less than 2 h. Similarity analysis of the selectivity of NTD in 39 tumor cell lines strongly supported the unique tumor cell specificity of NTD. Thus, these features indicate that NTD may be a promising antitumor drug for new combination chemotherapies.

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“…Previous studies showed that the expression of ABCA1 may be associated with resistance to an antitumor drug. The antitumor activity of nitidine, a benzophenanthridine alkaloid that has antitumor effects via the inhibition of topoisomerase I, was increased upon downregulation of ABCA1 (32). In addition, it was reported that ABCA1 may be related to the resistance to the antitumor activity of curcumin (33).…”

Section: Discussionmentioning

confidence: 97%

Factors involved in the cisplatin resistance of KCP-4 human epidermoid carcinoma cells

et al. 2013

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Abstract. KCP-4 is a cisplatin-resistant cell line established from human epidermoid carcinoma KB-3-1 cells. Although our previous study revealed that one of the mechanisms for cisplatin resistance in KCP-4 cells is the activation of NF-κB, its high resistance is considered to be induced by multiple mechanisms. In the present study, we explored other factors involved in the development of cisplatin resistance in KCP-4 cells. Since it has been reported that an unknown efflux pump exports cisplatin from KCP-4 cells in an ATP-dependent manner, we examined 48 types of ATP-binding cassette proteins as candidate cisplatin efflux transporters. The mRNA expression levels of ABCA1, ABCA3, ABCA7 and ABCB10 in KCP-4 cells were higher when compared to those in KB-3-1 cells. These expression levels in cisplatin-sensitive revertant KCP-4 cells (KCP-4R cells), were reduced in parallel with the sensitivity of these cells to cisplatin and their intracellular accumulation of cisplatin. Next, we investigated the occurrence of mutations in p53 in KCP-4 cells. We found a heterozygous missense mutation at codon 72 (p.Pro72Arg) in p53 of both KCP-4 and KB-3-1 cells, but the protein expression level of p53 in KCP-4 cells was higher when compared to that in KB-3-1. These results suggest that ABCA1, ABCA3, ABCA7 and ABCB10 are candidate genes for the cisplatin efflux transporter that is involved in the cisplatin resistance of KCP-4 cells, and that the mutation at codon 72 of p53 may contribute to the development of cisplatin resistance.

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Down-regulation of lipids transporter ABCA1 increases the cytotoxicity of Nitidine

Cited by 19 publications

References 23 publications

Enhanced cytotoxicity of nitidine against camptothecin-resistant A549 cells

Enhanced cytotoxicity of nitidine against camptothecin-resistant A549 cells

Tumor-Selective Cytotoxicity of Nitidine Results from Its Rapid Accumulation into Mitochondria

Factors involved in the cisplatin resistance of KCP-4 human epidermoid carcinoma cells

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