Molecular changes to HeLa cells on continuous exposure to SN-38, an active metabolite of irinotecan hydrochloride

Takara, Kohji; Kitada, Noriaki; Yoshikawa, Eri; Yamamoto, Kazuhiro; Horibe, Sayo; Sakaeda, Toshiyuki; Nishiguchi, Kohshi; Ohnishi, Noriaki; Yokoyama, Teruyoshi

doi:10.1016/j.canlet.2008.12.033

Cited by 20 publications

(36 citation statements)

References 28 publications

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“…In other human cancer clones selected for resistance to SN-38 via continuous exposure of parental cell lines to the drug in culture, overexpression of ABCG2 has also been reported for the sublines generated from MCF-7 (42, 43), MDA-MB-231 (43), the smallcell lung carcinoma PC-6 (17), the non-small cell lung adenocarcinoma H23 (44), and the cervical carcinoma HeLa (45). Cross-resistance of these sublines to doxorubicin varied somewhat, with the resistance ratio (IC 50 in resistant subline divided by IC 50 in the parental cell) being less than 1.3 for the sublines of PC-6 (17), 2.5 for the sublines of HeLa (45), and about 7.0 for the subline of H23 (44).…”

Section: Improved Efficacy Of Immu-132 When Combined With Yho-13351 Imentioning

confidence: 91%

Combining ABCG2 Inhibitors with IMMU-132, an Anti–Trop-2 Antibody Conjugate of SN-38, Overcomes Resistance to SN-38 in Breast and Gastric Cancers

Chang

Wang

Zalath

et al. 2016

Molecular Cancer Therapeutics

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Sacituzumab govitecan , an SN-38-conjugated antibody-drug conjugate, is showing promising therapeutic results in a phase I/II trial of patients with advanced Trop-2-expressing, metastatic, solid cancers. As members of the ATPbinding cassette (ABC) transporters confer chemotherapy resistance by active drug efflux, which is a frequent cause of treatment failure, we explored the use of known inhibitors of ABC transporters for improving the therapeutic efficacy of IMMU-132 by overcoming SN-38 resistance. Two human tumor cell lines made resistant to SN-38, MDA-MB-231-S120 (human breast cancer) and NCI-N87-S120 (human gastric cancer), were established by continuous exposure of the parental cells to stepwise increased concentrations of SN-38 and analyzed by flow cytometry for functional activities of ABCG2 and ABCB1, immunoblotting and qRT-PCR for the expression of ABCG2 at both protein and mRNA levels, and MTS assays for the potency of SN-38 alone or in combination with a modulator of ABC transporters. MDA-MB-231-S120 and NCI-N87-S120 displayed reduced sensitivity to SN-38 in vitro, with IC 50 values approximately 50-fold higher than parental MDA-MB-231 and NCI-N87 cells. The increase in drug resistance of both S120 cell populations is associated with the expression of functional ABCG2, but not ABCB1. Importantly, treatment of both S120 sublines with known ABCG2 inhibitors (fumitremorgin C, Ko143, and YHO-13351) restored toxicity of SN-38, and the combination of YHO-13351 with IMMU-132 increased the median survival of mice bearing NCI-N87-S120 xenografts. These results provide a rationale for combination therapy of IMMU-132 and inhibitors of ABC transporters, such as YHO-13351.

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Section: Improved Efficacy Of Immu-132 When Combined With Yho-13351 Imentioning

confidence: 91%

Combining ABCG2 Inhibitors with IMMU-132, an Anti–Trop-2 Antibody Conjugate of SN-38, Overcomes Resistance to SN-38 in Breast and Gastric Cancers

Chang

Wang

Zalath

et al. 2016

Molecular Cancer Therapeutics

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“…Previously, we established various types of resistant cells appropriate for examining the novel mechanism of resistance and techniques for reversing resistance (12,13). One type, HeLa/SN100, was selected from HeLa cells by exposure to an active metabolite of irinotecan hydrochloride, SN-38 (12).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…One type, HeLa/SN100, was selected from HeLa cells by exposure to an active metabolite of irinotecan hydrochloride, SN-38 (12). HeLa/SN100 cells overexpressed ABCG2/BCRP but not ABCB1/MDR1 (12). This is a useful tool for clarifying the details of the ABCG2/BCRP-mediated resistance mechanism and comparing it with other resistance mechanisms of paclitaxel-resistant (HeLa/TXL) or cisplatin-resistant (HeLa/ CDDP) cells established previously (13).…”

Section: Introductionmentioning

confidence: 99%

“…HeLa cells were seeded into culture flasks, grown in a humidified atmosphere containing 5% CO 2 at 37˚C, and subcultured with 0.05% trypsin-0.02% ethylenediamine-N,N,N',N'-tetraacetic acid (Invitrogen) at a density of 1x10 6 cells/25 cm 2 culture flasks. The HeLa/SN100 cells were previously established in our laboratory (12). HeLa/SN100 cells overexpressed ABCG2/BCRP but not ABCB1/MDR1, and showed resistance to irinotecan, topotecan and mitoxantrone (12).…”

Section: Introductionmentioning

confidence: 99%

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Differential effects of calcium antagonists on ABCG2/BCRP-mediated drug resistance and transport in SN-38-resistant HeLa cells

et al. 2011

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Abstract. The effects of 9 calcium antagonists on ABCG2/ BCRP-mediated resistance and transport were examined in HeLa and SN-38-resistant HeLa (HeLa/SN100) cells, overexpressing ABCG2/BCRP. Sensitivity to mitoxantrone, an ABCG2/BCRP substrate, in HeLa/SN100 cells was significantly reversed by the coexistence of the calcium antagonists, except for diltiazem and verapamil. The accelerated transport activity of Hoechst33342, an ABCG2/BCRP substrate, in HeLa/SN100 cells was significantly decreased by the presence of the calcium antagonists, except for diltiazem, nifedipine or verapamil, returning to the level of HeLa cells. The present study classifies the calcium antagonists into 3 categories: strong (benidipine, felodipine, nicardipine, nisoldipine and nitrendipine), moderate (amlodipine and nifedipine) and weak (diltiazem and verapamil) inhibitors of ABCG2/BCRP.

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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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Molecular changes to HeLa cells on continuous exposure to SN-38, an active metabolite of irinotecan hydrochloride

Cited by 20 publications

References 28 publications

Combining ABCG2 Inhibitors with IMMU-132, an Anti–Trop-2 Antibody Conjugate of SN-38, Overcomes Resistance to SN-38 in Breast and Gastric Cancers

Combining ABCG2 Inhibitors with IMMU-132, an Anti–Trop-2 Antibody Conjugate of SN-38, Overcomes Resistance to SN-38 in Breast and Gastric Cancers

Differential effects of calcium antagonists on ABCG2/BCRP-mediated drug resistance and transport in SN-38-resistant HeLa cells

Enhanced cytotoxicity of nitidine against camptothecin-resistant A549 cells

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