Research ArticleExperimental Studies

Quantitative Structure–Cytotoxicity Relationship of 2-(N-cyclicamino)chromone Derivatives

HAIXIA SHI, JUNKO NAGAI, TSUKASA SAKATSUME, KENJIRO BANDOW, NORIYUKI OKUDAIRA, HIROSHI SAKAGAMI, MINEKO TOMOMURA, AKITO TOMOMURA, YOSHIHIRO UESAWA, KOICHI TAKAO and YOSHIAKI SUGITA
Anticancer Research July 2018, 38 (7) 3897-3906; DOI: https://doi.org/10.21873/anticanres.12674

Abstract

Background/Aim: 4H-1-Benzopyran-4-ones (chromones) have provided backbone structure for the chemical synthesis of potent anticancer drugs. In this study, the cytotoxicity of fifteen 2-(N-cyclicamino)chromone derivatives was investigated and subjected to quantitative structure–activity relationship (QSAR) analysis. Materials and Methods: Cytotoxicity against four human oral squamous cell carcinoma cell lines and three oral normal mesenchymal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor specificity (TS) was evaluated by ratio of mean 50% cytotoxic concentration (CC50) against normal oral cells to that against human oral squamous cell carcinoma cell lines. Potency-selectivity expression (PSE) value was calculated by dividing the TS value by CC50 against tumor cells. Apoptosis induction was evaluated by morphological observation, western blot analysis and cell-cycle analysis. For QSAR analysis, a total of 3,089 physicochemicals, structural and quantum chemical features were calculated from the most stabilized structure optimized using Corina. Results: 7-Methoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one (5c) showed highest tumor-specificity, comparable with that of doxorubicin, without inducing apoptosis. Tumor-specificity of fifteen 2-(N-cyclicamino) chromones was correlated with molecular shape, especially 3D-structure. Conclusion: Chemical modification of 5c may be a potential choice for designing a new type of anticancer drugs.

4H-1-Benzopyran-4-one (chromone) are an important class of oxygenated heterocyclic compounds, since the core structure is found ubiquitously in the plant kingdom in notable amounts (1), and thus provides a backbone structure for the synthesis of various derivatives. 2-Aminochromone derivatives showed various biological activities including anti-inflammatory activity (2, 3), antimicrobial activity (3), phosphodiesterase inhibition (4, 5), modulation of DNA repair (6), inhibitors of DNA-dependent protein kinase and radiosensitization of a human tumor cell line (7) and new potential PET agents for imaging of DNA-dependent protein kinase (DNA-PK) in cancer (8). On the other hand, the investigation of their anticancer activity, using both human malignant and non-malignant cells, is limited.

We recently reported that (E)-3-[2-(4-hydroxyphenyl) ethenyl]-6-methoxy-4H-1-benzopyran-4-one (classified as 3-styrylchromones) (9), (E)-3-[2-(4-chlorophenyl)ethenyl]-7-methoxy-2H-1-benzopyran (classified as 3-styryl-2H-chromenes) (10), 2-(1H-indol-1-yl)-4H-1-benzopyran-4-one, 2-(1H-indol-1-yl)-7-methoxy-4H-1-benzopyran-4-one and 2-(1H-indol-1-yl)-6-methoxy-4H-1-benzopyran-4-one (classified as 2-azolylchromones) (11), showed much higher cytotoxicity against human oral squamous cell carcinoma (OSCC) cell lines than against human normal oral mesenchymal normal oral cells (gingival fibroblast, periodontal ligament fibroblast, pulp cell), yielding excellent tumor-specificity (TS) (TS=69, 60, >38, 24 and 24, respectively) (9-11) comparable with that of anti-cancer drugs (camptothecin, SN-38, doxorubicin, daunorubicin, etoposide, mitomycin C, 5-fluorouracil, docetaxel, melphalan and gefitinib) (TS=>1853, >979, 70, 55, 93, 31, >170, >10, >2708 and 4, respectively) (12). Furthermore, (E)-3-[2-(4-hydroxyphenyl)ethenyl]-6-methoxy-4H-1-benzopyran-4-one (9), and (E)-3-[2-(4-chlorophenyl)ethenyl]-7-methoxy-2H-1-benzopyran (10) showed much lower cytotoxicity against human normal oral epithelial cells (9, 10) as compared with these anticancer drugs (12).

Figure 1.
Figure 1.

Structure of fifteen 2-(N-cyclicamino)chromones.

In continuation of discovering new biological activities of chromone derivatives, a total of fifteen 2-(N-cyclicamino) chromone derivatives (Figure 1) were investigated for their cytotoxicity against four human OSCC cell lines and three human normal oral cells, and then subjected to quantitative structure–activity relationship (QSAR) analysis.

Materials and Methods

Materials. The following chemicals and reagents were obtained from the indicated companies: Dulbecco's modified Eagle's medium (DMEM), from GIBCO BRL (Grand Island, NY, USA); fetal bovine serum (FBS), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), doxorubicin, ribonuclease (RNase) A from Sigma-Aldrich Inc. (St. Louis, MO, USA); propidium iodide (PI), dimethyl sulfoxide (DMSO), actinomycin D (Act. D), 4% paraformaldehyde phosphate buffer solution (Wako Pure Chem. Ind., Osaka, Japan); Nonidet P-40 (NP-40) (Nakalai Tesque Inc., Kyoto, Japan); Culture plastic dishes and 96-well plates (TPP, Techno Plastic Products AG, Trasadingen, Switzerland).

Synthesis of 2-(N-cyclicamino)chromone derivatives. 2-(1-Piperidinyl)-4H-1-benzopyran-4-one (1a), 6-methoxy-2-(1-piperidinyl)-4H-1-benzopyran-4-one (1b), 7-methoxy-2-(1-piperidinyl)-4H-1-benzopyran-4-one (1c), 2-(4-phenyl-1-piperidinyl)-4H-1-benzopyran-4-one (2a), 6-methoxy-2-(4-phenyl-1-piperidinyl)-4H-1-benzopyran-4-one (2b), 7-methoxy-2-(4-phenyl-1-piperidinyl)-4H-1-benzopyran-4-one (2c), 2-(4-phenyl-1-piperazinyl)-4H-1-benzopyran-4-one (3a), 6-methoxy-2-(4-phenyl-1-piperazinyl)-4H-1-benzopyran-4-one (3b), 7-methoxy-2-(4-phenyl-1-piperazinyl)-4H-1-benzopyran-4-one (3c), 2-(4-methyl-1-piperazinyl)-4H-1-benzopyran-4-one (4a), 6-methoxy-2-(4-methyl-1-piperazinyl)-4H-1-benzopyran-4-one (4b), 7-methoxy-2-(4-methyl-1-piperazinyl)-4H-1-benzopyran-4-one (4c), 2-(4-morpholinyl)-4H-1-benzopyran-4-one (5a), 6-methoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one (5b), 7-methoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one (5c) were synthesized by the nucleophilic substitution reactions of 3-triazolylchromone derivatives (13) with selected cyclic secondary amines, according to previous methods (14). All compounds were dissolved in DMSO at 40 mM and stored at −20°C before use.

View this table:
Table I.

Cytotoxic activity of fifteen 2-(N-cyclicamino)chromones against oral malignant and non-malignant cells. Each value represents the mean of triplicate determinations. Two sets of TS and PSE values were determined using all malignant and non-malignant cells, or the pair of the cells derived from the same (gingival) tissue.

Cell culture. Human normal oral mesenchymal cells (human gingival fibroblast, HGF; human periodontal ligament fibroblast, HPLF; human pulp cells, HPC) were established from the first premolar tooth extracted from the lower jaw of a 12-year-old girl (15), and cells at 10-18 population doubling levels were used in this study. Human oral squamous cell carcinoma (OSCC) cell lines [Ca9-22 (derived from gingival tissue); HSC-2, HSC-3, HSC-4 (derived from tongue)] were purchased from Riken Cell Bank (Tsukuba, Japan). All of these cells were cultured at 37°C in DMEM supplemented with 10% heat-inactivated FBS, 100 units/ml, penicillin G and 100 μg/ml streptomycin sulfate under a humidified 5% CO2 atmosphere. Cell morphology was checked periodically under the light microscope (EVOS FL, ThermoFisher Scientific, Waltham, MA, USA).

Assay for cytotoxic activity. Cells were inoculated at 2×103 cells/0.1 ml in a 96-microwell plate. After 48 h, the medium was replaced with 0.1 ml of fresh medium containing different concentrations of single test compounds. Cells were incubated further for 48 h and the relative viable cell number was then determined by the MTT method (9-12). The relative viable cell number was determined by the absorbance of the cell lysate at 560 nm, using a microplate reader (Infinite F50R, TECAN, Männedorf, Switzerland). Control cells were treated with the same amounts of DMSO and the cell damage induced by DMSO was subtracted from that induced by test agents. The concentration of compound that reduced the viable cell number by 50% (CC50) was determined from the dose–response curve and the mean value of CC50 for each cell type was calculated from triplicate assays.

Calculation of tumor-selectivity index (TS). TS was calculated using the following equation: TS=mean CC50 against three normal oral cells/mean CC50 against for OSCC cell lines [(D/B) in Table I]. Since both Ca9-22 and HGF cells were derived from the gingival tissue (16), the relative sensitivity of these cells was also compared [(C/A) in Table I].

Calculation of potency-selectivity expression (PSE). PSE was calculated by the following equation: PSE=TS/CC50 against tumor cells ×100 [that is, (D/B2) ×100 (HGF, HPLF, HPC vs. Ca9-22, HSC-2, HSC-3, HSC-4) using all non-malignant and malignant cells, and (C/A2) ×100 (HGF vs. Ca9-22) using the pair of the cells from the same tissue (gingiva) (Table I).

Western blot analysis. Cells were washed with phosphate-buffered saline (PBS) and re-suspended in 50 mM Tris-HCl (pH 7.6), 150 mM NaCl, 1 mM EDTA, 0.1% sodium dodecyl sulfate (SDS), 0.5% deoxycholic acid, 1% NP-40 and protease inhibitors (RIPA buffer). After ultrasonication using Bioruptor (UCD-250; Cosmo Bio, Tokyo, Japan) for 12.5 min (10 sec on, 20 sec off) at the middle level of output (250 W) at 4°C, the soluble cellular extracts were recovered after centrifugation for 10 min at 16,000 × g. The protein concentration of each sample was determined using the BCA Protein Assay Reagent Kit (Thermo Fisher Scientific) and cell extracts were subjected to Western blot (WB) analysis. The blots were probed with anti-Poly (ADP-ribose) polymerase (PARP) antibody (Cell Signaling Technology Inc., Beverly, MD, USA), anti-caspase 3 antibody (Cell Signaling Technology Inc.), or anti-glyceraldehyde 3-phosphate dehydrogenase (GAPDH) antibody (Trevigen, Gaithersburg, MD, USA), followed by a horseradish peroxidase-conjugated anti-α-rabbit IgG secondary antibody (DAKO, Glostrup, Denmark). The immune complexes were visualized using Pierce Western Blotting Substrate Plus (Thermo Fisher Scientific). WB results were documented and quantified using ImageQuant LAS 500 (GE Healthcare, Tokyo, Japan) (17).

Figure 2.
Figure 2.

Cytotoxicity of 5c against four human OSCC cells lines and human normal oral cells. Ca9-22, HSC-2, HSC-3, HSC-4, HGF, HPLF and HPC (indicated by decreasing intensity of black color) were incubated for 48 h without (control) or with the indicated concentrations of 5c, and cell viability was determined by MTT method, and expressed as % of control. Each value represents mean±S.D. of triplicate assays.

Cell cycle analysis. Cells (approximately 106 cells) were harvested, fixed with 1% paraformaldehyde in phosphate-buffered saline without calcium and magnesium ions [PBS (−)]. Fixed cells were washed twice with PBS (−), and then treated for 30 min with 200 μl of 2 mg/ml RNase A (preheated for 10 min at 100°C to inactivate DNase) to degrade RNA. Cells were then washed twice with PBS (−) and stained for 15 min with 0.01% propidium iodide (PI) in the presence of 0.01% NP-40 in PBS (−) that prevents cell aggregation. After filtering through Falcon® cell strainers (40 μM) (Corning, NY, USA) to remove aggregated cells, PI-stained cells were subjected to cell sorting (SH800 Series, SONY Imaging Products and Solutions Inc., Atsugi, Kanagawa, Japan). Cell cycle analysis was performed with Cell Sorter Software version 2.1.2. SONY Imaging Products and Solution Inc.).

Estimation of CC50 values. Since the CC50 values had a distribution pattern close to a logarithmic normal distribution, we used the pCC50 (i.e., the −log CC50) for the comparison of the cytotoxicity between the compounds. The mean pCC50 values for normal cells and tumor cell lines were defined as N and T, respectively (10).

Calculation of chemical descriptors. The 3D-structure of each chemical structure (drawn by Marvin Sketch ver 16, ChemAxon, Budapest, Hungary, http://www.chemaxon.com) was optimized by CORINA Classic (Molecular Networks GmbH, Nürnberg, Germany) with forcefield calculations (amber-10: EHT) in Molecular Operating Environment (MOE) version 2018.0101 (Chemical Computing Group Inc., Quebec, Canada). The number of structural descriptors calculated from MOE (18) and Dragon 7.0 (19) (Kode srl., Pisa, Italy) after the elimination of overlapped descriptors were 293 and 2,796, respectively.

Figure 3.
Figure 3.

Production of enlarged cell population by 5c in HSC-2 cells. HSC-2 cells were incubated for 24 or 48 h with the indicated concentrations of 5c or 1 μM actinomycin D (Act. D, positive control), and then assessed for morphology under the light microscope (EVOS FL, ThermoFisher Scientific). Bar: 100 μm.

Statistical treatment. The relation among cytotoxicity, tumor specificity index and chemical descriptors was investigated using simple regression analyses by JMP Pro version 13.2.0 (SAS Institute Inc., Cary, NC, USA). The significance level was set at p<0.05.

Results

Cytotoxicity. A total of fifteen 2-(N-cyclicamino)chromone derivatives were synthesized, without (a series) or with introduction of methoxy group at the C-6 position (b series) or the C-7 position (c series) of benzopyran-4-one (chromone) ring attached by 1-piperidinyl (1a, 1b, 1c), 4-phenyl-1-piperidinyl (2a, 2b, 2c), 4-phenyl-1-piperazinyl (3a, 3b, 3c), 4-methyl-1-piperazinyl (4a, 4b, 4c) or 4-morpholinyl (5a, 5b, 5c) group at the C-2 position (Figure 1).

The effect of introduction of substituent groups at the C-2 position was first investigated on the cytotoxicity induction of chromone. Compound introduced with 4-phenyl-1-piperazinyl group (3a) showed the highest cytotoxicity against both OSCC cells and normal oral cells (mean CC50=130 and 225 μM, respectively), followed by compound with 4-phenyl-1-piperidinyl (2a) (282; 228 μM), 4-morpholinyl (5a) (354; 318 μM), 1-piperidinyl (1a) (398; 366 μM) and 4-methyl-1-piperazinyl group (4a) (400; 396 μM) (Table I).

Figure 4.
Figure 4.

Failure of caspase-3 activation by 5c in HSC-2 cells. HSC-2 cells were incubated for 24 h with the indicated concentrations of 5c or 1 μM actinomycin D (Act. D, positive control), and then investigated for apoptosis induction by western blot analysis.

Introduction of methoxy group to a-series compounds at the C-6 position yielded b-series compounds. Four b-series compounds (2b, 3b, 4b, 5b) except 1b did not increase, but rather slightly reduced the cytotoxicity of the corresponding a-series compound (Table I).

Figure 5.
Figure 5.

Failure of production of subG1 population by 5c. Cell-cycle analysis of HSC-2 cells treated for 24 h with the indicated concentrations of 5c or 1 μM actinomycin D (Act. D, positive control).

View this table:
Table II.

Number of descriptors that shows significant difference with T, N or T-N in ordinal condition (A), when 5c was eliminated (B) or common in both A and B.

Introduction of methoxy group to a-series compounds at the C-7 position yielded c-series compounds. 5c showed 63.3 (348/5.5)-fold higher cytotoxicity against OSCC cell lines as compared with (5a). 3c showed 3.0 (275/93)-fold higher cytotoxicity as compared with 3a. 1c, 2c and 4c showed comparable cytotoxicity with (1a, 2a, 4a) (Table I).

Tumor-specificity. Tumor-specificity (TS) was calculated by dividing the mean CC50 value towards three normal cells by the mean CC50 value towards four OSCC cell lines (D/B, Table I). Among fifteen compounds, 5c showed the highest tumor-specificity (TS=63.4), slightly higher than that of doxorubicin (TS=48.3). Dose-response curve of 5c showed that it was cytotoxic to OSCC cells, rather than cytostatic (Figure 2). 3c showed some tumor-specificity (TS=3.0), whereas TS values of other 13 compounds were less than 2 (Table I).

Figure 6.
Figure 6.

Determination of coefficient between chemical descriptors and cytotoxicity of fifteen 2-(N-cyclicamino)chromones against tumor cells (defined as T). The mean (pCC50 i.e., the −log CC50) values for tumor cell lines were defined as T.

Considering that HGF is the normal cell corresponding to cancer cell Ca9-22 (both derived from gingival tissues), TS values were also generated by dividing the average CC50 value towards HGF cells by the CC50 value towards Ca9-22 cells (C/A, Table I). 5c (TS=26.7) showed again the highest tumor-specificity, only slightly lower than that of doxorubicin (TS=33.2). 3c showed some tumor-specificity (TS=2.3) whereas TS values of other compounds were less than 2 (Table I).

PSE value. In order to identify the most promising compounds in terms of both good potencies and selectively cytotoxic, the potency-selectivity expression (PSE) values were calculated. 5c showed more than 364-fold (1156.34/3.18) (calculated with all malignant and non-malignant cells; (D/B2)×100) or 108-fold higher PSE value (291.68/2.69) (calculated with cells from the same tissue; (C/A2)×100) than 3c and other 13 compounds, although doxorubicin having lower CC50 values against OSCC cell lines showed much higher PSE values (Table I).

Type of cell death induced by 5c. When HSC-2 cells were incubated for 24 h with increasing concentrations (20, 40, 80 or 160 μM) of 5c, cells became gradually enlarged (upper column in Figure 3). Cell enlargement and damage were more pronounced when incubation time was prolonged to 48 h (lower column in Figure 3). In contrast, actinomycin D (Act.D) treatment induced cell shrinkage, characteristic to apoptosis (Figure 3).

Western blot analysis demonstrated that 5c did not produce caspase-3 activation, as evidenced by lack of cleavage of poly (ADP-ribose) polymerase (PARP) and capspase-3, in contrast to actinomycin D treatment (Figure 4).

Cell cycle analysis demonstrated that actinomycin D, but not 5c, produced sub-G1 cell population that is characteristic to apoptotic cells. 5c increased the relative number of G1 phase cells, while it reduced the number of S and M phase cells (Figure 5). These data reduced the possibility of apoptosis induction by 5c.

Computational analysis. We next performed the QSAR analysis of fifteen 2-(N-cyclicamino)chromones in regards to their cytotoxicity against tumor cells and normal cells. Since 5c shows remarkable tumor selectivity, we selected descriptors by two approaches, using all fifteen compounds or fourteen compounds excluding 5c. We chose descriptors that show significant correlation with each of T, N, and T-N in both analyses (Table II). Among a total of 3089 descriptors, 13 descriptors correlated well with cytotoxicity and tumor specificity (Table III).

Cytotoxicity of fifteen 2-(N-cyclicamino)chromones against human OSCC cell lines was correlated positively with SpPosA_B(m) (topological shape and size) (r2=0.400, p=0.0113), SpPosA_B(e) (topological shape and electric state) (r2=0.305, p=0.0121), Mor17v (3D shape and size) (r2=0.320, p=0.0280), Mor17m (3D shape and size) (r2=0.317, p=0.0287), VE1sign_B(v) (topological shape and size) (r2=0.292, p=0.0376), while negatively with GCUT_SLOGP_1 (topological shape) (r2=0.372, p=0.0158) (Figure 6).

Figure 7.
Figure 7.

Determination of coefficient between chemical descriptors and cytotoxicity of fifteen 2-(N-cyclicamino)chromones against normal cells (defined as N). The mean (pCC50 i.e., the −log CC50) values for normal cells were defined as N.

View this table:
Table III.

Properties of descriptors that significantly affects the cytotoxicity against tumor cells (T), normal cells (N) and tumor-specificity (T-N).

Figure 8.
Figure 8.

Determination of coefficient between chemical descriptors and tumor specificity of fifteen 2-(N-cyclicamino)chromones (defined as T–N).

Cytotoxicity of fifteen 2-(N-cyclicamino)chromones against human normal oral mesenchymal cells was correlated negatively with Mor32u (3D shape) (r2=0.728, p<0.0001), Mor32e (3D shape and electoric state) (r2=0.726, p<0.0001), JGI4 (topological shape and electric state) (r2=0.691, p=0.0001), and SPH (shape) (r2=0.685, p=0.0001) while positively with VR2_G/D (3D shape) (r2=0.693, p=0.0001) and VR2_G (3D shape) (r2=0.686, p=0.0001) (Figure 7).

Tumor specificity of fifteen 2-(N-cyclicamino)chromones was correlated negatively with Mor22m (3D shape) (r2=0.367, p=0.0166) and GCUT_SLOGP_1 (topological shape) (r2=0.360, p=0.0180), while positively with Mor17v (3D shape and size) (r2=0.290, p=0.0384) and Mor17m (3D shape and size) (r2=0.266, p=0.0491) (Figure 8).

Discussion

The present study demonstrated that among fifteen 2-(N-cyclicamino)chromones, 7-methoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one (5c) showed the highest tumor-specificity, comparable with that of doxorubicin (Table I). As far as we know, there is no report that has investigated the biological activity of this compound. Incubation of HSC-2 cells for 48 h with 5c at 100 μM reduced the cell viability to 5% of control, suggesting its action seems to be cytotoxic rather than cytostatic. We concluded that 5c did not induce apoptotic cell death, based on the next evidences: (i) it induced cell enlargement while actinomycin D induced cell shrinkage (Figure 3), (ii) it did not activate caspase-3 while actinomycin D induced activated caspase-3 (based on the induction of cleaved product of PARP and caspase-3) (Figure 4), (iii) it did not produce sub G1 population while actinomycin D produced sub G1 population (Figure 5). There are many types of cell death such as intrinsic and extrinsic apoptosis, oncosis, necroptosis, parthanatos, ferroptosis, sarmoptosis, autophagic cell death, autosis, autolysis, paraptosis, pyroptosis, phagoptosis, and mitochondrial permeability transition (20). Further study is needed regarding which type of cell death 5c induces in human OSCC cell lines.

QSAR analysis demonstrated that cytotoxicity of fifteen 2-(N-cyclicamino)chromones against tumor cell lines was correlated positively with SpPosA_B(m) (mass), SpPosA_B(e) (Sanderson electronegativity), Mor17v (van der Waals volume), Mor17m (mass), VE1sign_B(v) (van der Waals volume), while negatively with GCUT_SLOGP_1 (log P) (Figure 6). Their tumor specificity was reflected by Mor17v (van der Waals volume) and Mor17m (mass), while negatively with Mor22m (mass) and GCUT_SLOGP_1 (log P) (Figure 8). Taken together these data suggest that both their cytotoxicity against tumor cells and tumor-specificity are positively related with chemical descriptors that reflect molecular shape, especially 3D-structure (Figure 7). Chemical modification using 5c as a lead compound may be a potential choice for designing a new type of anticancer drugs.

Acknowledgements

This work was partially supported by KAKENHI from the Japan Society for the Promotion of Science (JSPS) (15K08111, 16K11519).

Footnotes

  • Conflicts of Interest

    The Authors wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

  • Received May 19, 2018.
  • Revision received June 4, 2018.
  • Accepted June 6, 2018.

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Quantitative Structure–Cytotoxicity Relationship of 2-(N-cyclicamino)chromone Derivatives
HAIXIA SHI, JUNKO NAGAI, TSUKASA SAKATSUME, KENJIRO BANDOW, NORIYUKI OKUDAIRA, HIROSHI SAKAGAMI, MINEKO TOMOMURA, AKITO TOMOMURA, YOSHIHIRO UESAWA, KOICHI TAKAO, YOSHIAKI SUGITA
Anticancer Research Jul 2018, 38 (7) 3897-3906; DOI: 10.21873/anticanres.12674
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