Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer
Identifieur interne : 000703 ( Pmc/Checkpoint ); précédent : 000702; suivant : 000704Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer
Auteurs : Jade H.-M. Hsu [Taïwan] ; Peter M.-H. Chang [Taïwan] ; Tai-Shan Cheng [Taïwan] ; Yu-Lun Kuo [Taïwan] ; Alexander T.-H. Wu [Taïwan] ; Thu-Ha Tran [Taïwan] ; Yun-Hsuan Yang [Taïwan] ; Jing-Ming Chen [Taïwan] ; Yu-Chen Tsai [Taïwan] ; Yeh-Shiu Chu [Taïwan] ; Tse- Hung Huang [Taïwan] ; Chi-Ying F. Huang [Taïwan] ; Jin-Mei Lai [Taïwan]Source :
- Cancers [ 2072-6694 ] ; 2019.
Abstract
Low response rate and recurrence are common issues in lung cancer; thus, identifying a potential compound for these patients is essential. Utilizing an in silico screening method, we identified withaferin A (WA), a cell-permeable steroidal lactone initially extracted from
Url:
DOI: 10.3390/cancers11071003
PubMed: 31319622
PubMed Central: 6678286
Affiliations:
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<front><div type="abstract" xml:lang="en"><p>Low response rate and recurrence are common issues in lung cancer; thus, identifying a potential compound for these patients is essential. Utilizing an in silico screening method, we identified withaferin A (WA), a cell-permeable steroidal lactone initially extracted from <italic>Withania somnifera</italic>
, as a potential anti–lung cancer and anti–lung cancer stem-like cell (CSC) agent. First, we demonstrated that WA exhibited potent cytotoxicity in several lung cancer cells, as evidenced by low IC<sub>50</sub>
values. WA concurrently induced autophagy and apoptosis and the activation of reactive oxygen species (ROS), which plays an upstream role in mediating WA-elicited effects. The increase in p62 indicated that WA may modulate the autophagy flux followed by apoptosis. In vivo research also demonstrated the anti-tumor effect of WA treatment. We subsequently demonstrated that WA could inhibit the growth of lung CSCs, decrease side population cells, and inhibit lung cancer spheroid-forming capacity, at least through downregulation of mTOR/STAT3 signaling. Furthermore, the combination of WA and chemotherapeutic drugs, including cisplatin and pemetrexed, exerted synergistic effects on the inhibition of epidermal growth factor receptor (EGFR) wild-type lung cancer cell viability. In addition, WA can further enhance the cytotoxic effect of cisplatin in lung CSCs. Therefore, WA alone or in combination with standard chemotherapy is a potential treatment option for EGFR wild-type lung cancer and may decrease the occurrence of cisplatin resistance by inhibiting lung CSCs.</p>
</div>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cancers (Basel)</journal-id>
<journal-id journal-id-type="iso-abbrev">Cancers (Basel)</journal-id>
<journal-id journal-id-type="publisher-id">cancers</journal-id>
<journal-title-group><journal-title>Cancers</journal-title>
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<issn pub-type="epub">2072-6694</issn>
<publisher><publisher-name>MDPI</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31319622</article-id>
<article-id pub-id-type="pmc">6678286</article-id>
<article-id pub-id-type="doi">10.3390/cancers11071003</article-id>
<article-id pub-id-type="publisher-id">cancers-11-01003</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
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<title-group><article-title>Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer</article-title>
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<given-names>Yu-Lun</given-names>
</name>
<xref ref-type="aff" rid="af5-cancers-11-01003">5</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-0178-6530</contrib-id>
<name><surname>Wu</surname>
<given-names>Alexander T.-H.</given-names>
</name>
<xref ref-type="aff" rid="af6-cancers-11-01003">6</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-2273-2793</contrib-id>
<name><surname>Tran</surname>
<given-names>Thu-Ha</given-names>
</name>
<xref ref-type="aff" rid="af4-cancers-11-01003">4</xref>
<xref ref-type="aff" rid="af7-cancers-11-01003">7</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-1185-7547</contrib-id>
<name><surname>Yang</surname>
<given-names>Yun-Hsuan</given-names>
</name>
<xref ref-type="aff" rid="af8-cancers-11-01003">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Jing-Ming</given-names>
</name>
<xref ref-type="aff" rid="af9-cancers-11-01003">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tsai</surname>
<given-names>Yu-Chen</given-names>
</name>
<xref ref-type="aff" rid="af1-cancers-11-01003">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-5388-380X</contrib-id>
<name><surname>Chu</surname>
<given-names>Yeh-Shiu</given-names>
</name>
<xref ref-type="aff" rid="af10-cancers-11-01003">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Huang</surname>
<given-names>Tse- Hung</given-names>
</name>
<xref ref-type="aff" rid="af11-cancers-11-01003">11</xref>
<xref ref-type="aff" rid="af12-cancers-11-01003">12</xref>
<xref ref-type="aff" rid="af13-cancers-11-01003">13</xref>
<xref ref-type="aff" rid="af14-cancers-11-01003">14</xref>
<xref rid="c1-cancers-11-01003" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-4898-4937</contrib-id>
<name><surname>Huang</surname>
<given-names>Chi-Ying F.</given-names>
</name>
<xref ref-type="aff" rid="af1-cancers-11-01003">1</xref>
<xref ref-type="aff" rid="af4-cancers-11-01003">4</xref>
<xref rid="c1-cancers-11-01003" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-4893-3101</contrib-id>
<name><surname>Lai</surname>
<given-names>Jin-Mei</given-names>
</name>
<xref ref-type="aff" rid="af8-cancers-11-01003">8</xref>
<xref ref-type="aff" rid="af9-cancers-11-01003">9</xref>
<xref ref-type="aff" rid="af15-cancers-11-01003">15</xref>
<xref rid="c1-cancers-11-01003" ref-type="corresp">*</xref>
</contrib>
</contrib-group>
<aff id="af1-cancers-11-01003"><label>1</label>
Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, Taiwan</aff>
<aff id="af2-cancers-11-01003"><label>2</label>
Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei 112, Taiwan</aff>
<aff id="af3-cancers-11-01003"><label>3</label>
Faculty of Medicine, National Yang-Ming University, Taipei 112, Taiwan</aff>
<aff id="af4-cancers-11-01003"><label>4</label>
Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan</aff>
<aff id="af5-cancers-11-01003"><label>5</label>
Department of Computer Science and Information Engineering, National Taiwan University, Taipei 106, Taiwan</aff>
<aff id="af6-cancers-11-01003"><label>6</label>
The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan</aff>
<aff id="af7-cancers-11-01003"><label>7</label>
Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 112, Taiwan</aff>
<aff id="af8-cancers-11-01003"><label>8</label>
The Ph.D. Program in Pharmaceutical Biotechnology, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan</aff>
<aff id="af9-cancers-11-01003"><label>9</label>
Graduate Institute of Applied Science and Engineering, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan</aff>
<aff id="af10-cancers-11-01003"><label>10</label>
Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan</aff>
<aff id="af11-cancers-11-01003"><label>11</label>
Graduate Institute of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Chang Gung University, Taoyuan 333, Taiwan</aff>
<aff id="af12-cancers-11-01003"><label>12</label>
School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei 110, Taiwan</aff>
<aff id="af13-cancers-11-01003"><label>13</label>
Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung 204, Taiwan</aff>
<aff id="af14-cancers-11-01003"><label>14</label>
Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan</aff>
<aff id="af15-cancers-11-01003"><label>15</label>
Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan</aff>
<author-notes><corresp id="c1-cancers-11-01003"><label>*</label>
Correspondence: <email>kchuang@cgmh.org.tw</email>
(T.H.H.); <email>cyhuang5@ym.edu.tw</email>
(C.-Y.F.H.); <email>jmlai@mail.fju.edu.tw</email>
(J.-M.L.); Tel.: +886-2-2431-3131 (ext. 2777) (T.H.H.); +886-2-2826-7904 (C.-Y.F.H.); +886-2-2905-3595 (J.-M.L.); Fax: +886-2-2431-3161 (T.H.H.); +886-2-822-4045 (C.-Y.F.H.); +886-2-2905-3595 (J.-M.L.)</corresp>
</author-notes>
<pub-date pub-type="epub"><day>17</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><month>7</month>
<year>2019</year>
</pub-date>
<volume>11</volume>
<issue>7</issue>
<elocation-id>1003</elocation-id>
<history><date date-type="received"><day>27</day>
<month>6</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>15</day>
<month>7</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© 2019 by the authors.</copyright-statement>
<copyright-year>2019</copyright-year>
<license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
).</license-p>
</license>
</permissions>
<abstract><p>Low response rate and recurrence are common issues in lung cancer; thus, identifying a potential compound for these patients is essential. Utilizing an in silico screening method, we identified withaferin A (WA), a cell-permeable steroidal lactone initially extracted from <italic>Withania somnifera</italic>
, as a potential anti–lung cancer and anti–lung cancer stem-like cell (CSC) agent. First, we demonstrated that WA exhibited potent cytotoxicity in several lung cancer cells, as evidenced by low IC<sub>50</sub>
values. WA concurrently induced autophagy and apoptosis and the activation of reactive oxygen species (ROS), which plays an upstream role in mediating WA-elicited effects. The increase in p62 indicated that WA may modulate the autophagy flux followed by apoptosis. In vivo research also demonstrated the anti-tumor effect of WA treatment. We subsequently demonstrated that WA could inhibit the growth of lung CSCs, decrease side population cells, and inhibit lung cancer spheroid-forming capacity, at least through downregulation of mTOR/STAT3 signaling. Furthermore, the combination of WA and chemotherapeutic drugs, including cisplatin and pemetrexed, exerted synergistic effects on the inhibition of epidermal growth factor receptor (EGFR) wild-type lung cancer cell viability. In addition, WA can further enhance the cytotoxic effect of cisplatin in lung CSCs. Therefore, WA alone or in combination with standard chemotherapy is a potential treatment option for EGFR wild-type lung cancer and may decrease the occurrence of cisplatin resistance by inhibiting lung CSCs.</p>
</abstract>
<kwd-group><kwd>non-small-cell lung cancer</kwd>
<kwd>withaferin A</kwd>
<kwd>connectivity map</kwd>
<kwd>synergistic effect</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group><fig id="cancers-11-01003-f001" orientation="portrait" position="float"><label>Figure 1</label>
<caption><p>Identification of withaferin A (WA) as an anti–lung cancer agent using genomic approaches. (<bold>A</bold>
) Yang Ming, Eagle, and NTU lung adenocarcinoma gene expression profiles were used for analysis. An intensity of microarray <50 implies a “cut value 50”, which indicates that the array intensities that are <50 after normalization will be rounded up to 50. To determine the effective criteria for selecting potential drugs, three methods were used to select gene signatures and create potential drug lists. Drugs appeared by top-ranked frequency when searching the CMap with significantly negative scores (<italic>p</italic>
< 0.05, enrichment score <0) and were listed and compared with each other. Drugs with a frequency greater than 20% were selected based on three criteria. The results indicate that these compounds may potentially reverse the non-small-cell lung cancer (NSCLC) gene signature to the nonmalignant counterpart gene signature. (<bold>B</bold>
) Of the 57 intersected compounds, WA was selected to test the IC<sub>50</sub>
at 48 h in NSCSC cells (<italic>n</italic>
= 3). The epidermal growth factor receptor (EGFR) mutation statuses of these cells were also included. SAM: significance analysis of microarrays; WT=wildtype.</p>
</caption>
<graphic xlink:href="cancers-11-01003-g001"></graphic>
</fig>
<fig id="cancers-11-01003-f002" orientation="portrait" position="float"><label>Figure 2</label>
<caption><p>WA treatment induces autophagy in lung cancer cell lines. (<bold>A</bold>
) H1975 cells treated with WA at indicated concentrations for 24 h or 48 h. Western blot analysis revealed an increase in the cleavage of caspase 3 (<italic>n</italic>
= 3). (<bold>B</bold>
) (Above) Representative images of ROS levels in various treatment groups. H1975 cells treated with WA at a concentration of 2 µM for 30 min or 24 h. A strong ROS inducer, H<sub>2</sub>
O<sub>2</sub>
, was used as a positive control and compared with WA. (Below) Quantitative analysis of the average fluorescence intensity presented as a fold-change (mean ± SEM) compared with the vehicle treatment group (DMSO). Approximately 30 cells were analyzed for each treatment group in three independent experiments * <italic>p</italic>
< 0.05 vs. control; # <italic>p</italic>
< 0.05 drug treatment with vs. without NAC (<italic>N</italic>
-acetyl-L-cysteine). (<bold>C</bold>
) WA induced autophagy in H1975 cells in a time-dependent manner, from 4–24 h after 2-µM WA treatment (<italic>n</italic>
= 3). (<bold>D</bold>
) (Left) Representative images of acridine orange staining in H1975 cells treated with DMSO, 2 μM WA, 5 mM NAC, and a combination of WA and NAC for 24 h. (Right) Quantitative analysis of acridine orange staining flow cytometry results from three lung cancer cell lines: H441, H1975, and CL152 (<italic>n</italic>
= 3). (<bold>E</bold>
) (Left) Representative images of PI-Annexin-V staining in H1975 cells treated with DMSO, 2 μM WA, 5 mM NAC, and a combination of WA and NAC for 48 h. (Right) Quantitative analysis of PI-Annexin-V staining flow cytometry results from three lung cancer cell lines: H441, H1975, and CL152 (<italic>n</italic>
= 3). (<bold>F</bold>
) Cell viability results of CL141, H441, H1975, and CL152 treated with WA (at 0.5, 1, and 2 µM) with or without 5 mM NAC (<italic>n</italic>
= 3). (<bold>G</bold>
) NAC suppressed WA-induced autophagy and apoptosis activation as indicated by the western blot analysis of H1975 cells (<italic>n</italic>
= 3).</p>
</caption>
<graphic xlink:href="cancers-11-01003-g002"></graphic>
</fig>
<fig id="cancers-11-01003-f003" orientation="portrait" position="float"><label>Figure 3</label>
<caption><p>WA interrupts NRF2-KEAP1 interaction in NSCLC cells. (<bold>A</bold>
) H1975 cells were treated with 2 μM WA for 30 min or 24 h. NRF2 and KEAP1 interactions were detected using the Duolink proximity ligation assay (PLA) kit. (Left) Representative images of each treatment with the deep red blob signal; NRF2-KEAP1 interactions were detected in the cytoplasm of H1975 cells. (Right) Quantitative analysis of PLA results; the blob number is presented as blobs/cell. * <italic>p</italic>
< 0.05 vs. control. (<bold>B</bold>
) WA treatment upregulated KEAP1 and downregulated NRF2 in H1975 cells (<italic>n</italic>
= 3).</p>
</caption>
<graphic xlink:href="cancers-11-01003-g003"></graphic>
</fig>
<fig id="cancers-11-01003-f004" orientation="portrait" position="float"><label>Figure 4</label>
<caption><p>Noninvasive imaging of WA-mediated anti-lung tumorigenesis in vivo. (<bold>A</bold>
) Semiquantitative analysis of tumor burden with and without WA treatment. Fold changes in bioluminescence (BLI) from both the control and WA groups were determined. WA-treated mice exhibited a significantly lower change in bioluminescence over six weeks when compared with control mice. ** <italic>p</italic>
< 0.01 vs. control. (<bold>B</bold>
) Kaplan–Meier survival curves indicated that mice receiving WA treatment had a better survival rate than controls over the six-week experimental period. (<bold>C</bold>
) Longitudinal body weight monitoring revealed no significant difference between the control and WA-treated animals and suggesting no apparent systematic cytotoxicity at the dosage used in this study.</p>
</caption>
<graphic xlink:href="cancers-11-01003-g004"></graphic>
</fig>
<fig id="cancers-11-01003-f005" orientation="portrait" position="float"><label>Figure 5</label>
<caption><p>Identification of WA as an anti–lung cancer stem cell agent using GSEA analysis. (<bold>A</bold>
) In GSEA analysis, WA drug signature appears to be the reverse of the embryonic stem cell module from Wong’s study, which is similar to the expression of CSCs. (<bold>B</bold>
) In CL141 sphere cells, the protein expression of CD133, ALDH1A1, and Nanog was upregulated compared with the expression in their parental CL141 cells (<italic>n</italic>
= 3). (<bold>C</bold>
) WA treatment for 48 h significantly reduced the cell viability of CL141 sphere cells (<italic>n</italic>
= 3). (<bold>D</bold>
) CL141 sphere cells were treated with 0.5 µM WA for 24 h. Whole-cell lysates were resolved by SDS-PAGE and immunoblotted with specific antibodies, as indicated. WA inhibited mTOR and STAT3 activity, as indicated by the reduction of phospho-mTOR and STAT3 levels in CL141 sphere cells (<italic>n</italic>
= 3). (<bold>E</bold>
) H441, CL97, and H1975 cells were treated with 1 µM WA for 24 h, and the corresponding side population (SP) cells were gated after being stained with Hoechst 33342. (<bold>F</bold>
) Quantitative analysis results indicate that WA decreased SP cells in lung cancer cells tested (<italic>n</italic>
≥ 2). (<bold>G</bold>
) To analyze the effect of WA on sphere formation, H441 cells were cultured in stem cell medium before being treated with the indicated concentrations of WA for five days. The sphere number decreased in a dose-dependent manner after WA treatment (<italic>n</italic>
= 4). ** <italic>p</italic>
< 0.01, *** <italic>p</italic>
< 0.001 vs. control.</p>
</caption>
<graphic xlink:href="cancers-11-01003-g005"></graphic>
</fig>
<fig id="cancers-11-01003-f006" orientation="portrait" position="float"><label>Figure 6</label>
<caption><p>Synergy analysis of the interaction between WA and chemotherapy drugs in various lung cancer cell lines. (<bold>A</bold>
) To analyze the synergistic effect of WA combined with chemotherapy drugs (pemetrexed, cisplatin, and gemcitabine), cells were exposed to 0.5 µM WA and 5, 10, or 20 µM chemotherapy drugs simultaneously for 48 h in A549, CL141, CL152, and H1299 cells (<italic>n</italic>
= 3). (<bold>B</bold>
) The cytotoxic effect and synergistic effect of WA combined with cisplatin were in constant ratio combination (1:10) on A549 cells for the 48-h treatment. The values of the CI were as follows: CI > 1, antagonism; CI = 1, additivity; CI < 1, synergism. The lowest CI value indicated the best synergistic effect of the combination of two drugs for the inhibition of cell viability. (<bold>C</bold>
) H1975 cells were treated without or with WA and/or cisplatin as indicated for 24 h. Subsequently, cell lysates were harvested for the detection of caspase 3, pSTAT3/STAT3, p-mTOR/mTOR, and beta-tubulin by immunoblotting.</p>
</caption>
<graphic xlink:href="cancers-11-01003-g006"></graphic>
</fig>
<fig id="cancers-11-01003-f007" orientation="portrait" position="float"><label>Figure 7</label>
<caption><p>Combination of WA and cisplatin increases the ability of reducing cancer stem cell-related features as compare to cisplatin alone. (<bold>A</bold>
) H441 sphere cells were treated without or with cisplatin (1 µM) and WA (0.25, 0.375, or 0.5 µM) as indicated for five days. Although cisplatin treatment did not reduce the sphere cell number, it further enhanced the cytotoxic effect of WA (at 0.375 and 0.5 µM). * <italic>p</italic>
< 0.05; ** <italic>p</italic>
< 0.01; *** <italic>p</italic>
< 0.001 vs. control. In addition, cotreatment with WA (0.5 µM) and cisplatin had better effects compared with treatment with only 0.5 µM WA (<italic>n</italic>
= 3). # <italic>p</italic>
< 0.05 vs. corresponding dose of WA alone. (<bold>B</bold>
) The mean fluorescence intensity of ALDH<sup>+</sup>
cells was tested after A549 cells were treated with 1 µM WA, 1 µM cisplatin, or their combination (<italic>n</italic>
= 4). * <italic>p</italic>
< 0.05 vs. control.</p>
</caption>
<graphic xlink:href="cancers-11-01003-g007"></graphic>
</fig>
<table-wrap id="cancers-11-01003-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">cancers-11-01003-t001_Table 1</object-id>
<label>Table 1</label>
<caption><p>The calculated combination index (CI) of synergistic interactions between withaferin A and chemotherapy drugs in NSCLC.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Cell Line</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">WA (µM)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">(µM)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Pemetrexed<break></break>
CI</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Cisplatin<break></break>
CI</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Gemcitabine<break></break>
CI</th>
</tr>
</thead>
<tbody><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">A549</td>
<td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">0.5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.15 ± 0.17</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.39 ± 0.12</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.63 ± 0.04</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.23 ± 0.05</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.83 ± 0.03</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.72 ± 0.15</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">20</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.11 ± 0.32</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.86 ± 0.04</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.56 ± 0.11</td>
</tr>
<tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">CL141</td>
<td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">0.5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.56 ± 0.01</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.51 ± 0.01</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.97 ± 0.09</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.60 ± 0.02</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.62 ± 0.03</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.76 ± 0.05</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">20</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.69 ± 0.12</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.83 ± 0.09</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.73 ± 0.09</td>
</tr>
<tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">CL152</td>
<td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">0.5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.59 ± 0.03</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.60 ± 0.02</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.15 ± 0.02</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.57 ± 0.05</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.68 ± 0.03</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.84 ± 0.06</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">20</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.53 ± 0.05</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.00 ± 0.05</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.85 ± 0.09</td>
</tr>
<tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">H1299</td>
<td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">0.5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.73 ± 0.05</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.35 ± 0.02</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.08 ± 0.09</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.46 ± 0.02</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.31 ± 0.05</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.72 ± 0.11</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">20</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.47 ± 0.02</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.18 ± 0.04</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.72 ± 0.12</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p>The calculated combination index (CI) determined by CompuSyn software. CI < 1.0 suggests a synergistic interaction between the two agents.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
<affiliations><list><country><li>Taïwan</li>
</country>
</list>
<tree><country name="Taïwan"><noRegion><name sortKey="Hsu, Jade H M" sort="Hsu, Jade H M" uniqKey="Hsu J" first="Jade H.-M." last="Hsu">Jade H.-M. Hsu</name>
</noRegion>
<name sortKey="Chang, Peter M H" sort="Chang, Peter M H" uniqKey="Chang P" first="Peter M.-H." last="Chang">Peter M.-H. Chang</name>
<name sortKey="Chang, Peter M H" sort="Chang, Peter M H" uniqKey="Chang P" first="Peter M.-H." last="Chang">Peter M.-H. Chang</name>
<name sortKey="Chen, Jing Ming" sort="Chen, Jing Ming" uniqKey="Chen J" first="Jing-Ming" last="Chen">Jing-Ming Chen</name>
<name sortKey="Cheng, Tai Shan" sort="Cheng, Tai Shan" uniqKey="Cheng T" first="Tai-Shan" last="Cheng">Tai-Shan Cheng</name>
<name sortKey="Chu, Yeh Shiu" sort="Chu, Yeh Shiu" uniqKey="Chu Y" first="Yeh-Shiu" last="Chu">Yeh-Shiu Chu</name>
<name sortKey="Huang, Chi Ying F" sort="Huang, Chi Ying F" uniqKey="Huang C" first="Chi-Ying F." last="Huang">Chi-Ying F. Huang</name>
<name sortKey="Huang, Chi Ying F" sort="Huang, Chi Ying F" uniqKey="Huang C" first="Chi-Ying F." last="Huang">Chi-Ying F. Huang</name>
<name sortKey="Huang, Tse Hung" sort="Huang, Tse Hung" uniqKey="Huang T" first="Tse- Hung" last="Huang">Tse- Hung Huang</name>
<name sortKey="Huang, Tse Hung" sort="Huang, Tse Hung" uniqKey="Huang T" first="Tse- Hung" last="Huang">Tse- Hung Huang</name>
<name sortKey="Huang, Tse Hung" sort="Huang, Tse Hung" uniqKey="Huang T" first="Tse- Hung" last="Huang">Tse- Hung Huang</name>
<name sortKey="Huang, Tse Hung" sort="Huang, Tse Hung" uniqKey="Huang T" first="Tse- Hung" last="Huang">Tse- Hung Huang</name>
<name sortKey="Kuo, Yu Lun" sort="Kuo, Yu Lun" uniqKey="Kuo Y" first="Yu-Lun" last="Kuo">Yu-Lun Kuo</name>
<name sortKey="Lai, Jin Mei" sort="Lai, Jin Mei" uniqKey="Lai J" first="Jin-Mei" last="Lai">Jin-Mei Lai</name>
<name sortKey="Lai, Jin Mei" sort="Lai, Jin Mei" uniqKey="Lai J" first="Jin-Mei" last="Lai">Jin-Mei Lai</name>
<name sortKey="Lai, Jin Mei" sort="Lai, Jin Mei" uniqKey="Lai J" first="Jin-Mei" last="Lai">Jin-Mei Lai</name>
<name sortKey="Tran, Thu Ha" sort="Tran, Thu Ha" uniqKey="Tran T" first="Thu-Ha" last="Tran">Thu-Ha Tran</name>
<name sortKey="Tran, Thu Ha" sort="Tran, Thu Ha" uniqKey="Tran T" first="Thu-Ha" last="Tran">Thu-Ha Tran</name>
<name sortKey="Tsai, Yu Chen" sort="Tsai, Yu Chen" uniqKey="Tsai Y" first="Yu-Chen" last="Tsai">Yu-Chen Tsai</name>
<name sortKey="Wu, Alexander T H" sort="Wu, Alexander T H" uniqKey="Wu A" first="Alexander T.-H." last="Wu">Alexander T.-H. Wu</name>
<name sortKey="Yang, Yun Hsuan" sort="Yang, Yun Hsuan" uniqKey="Yang Y" first="Yun-Hsuan" last="Yang">Yun-Hsuan Yang</name>
</country>
</tree>
</affiliations>
</record>
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