An isoxazole derivative ShU00238 suppresses colorectal cancer growth through miRNAs regulation

Article abstract of DOI:10.3390/molecules24122335

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Isoxazoline and isoxazole derivatives represent an important class of five-membered heterocycles, which play a pivotal role in drug discovery. In our previous study, we develop

Full text of DOI:10.3390/molecules24122335

molecules
Article
An Isoxazole Derivative SHU00238 Suppresses
Colorectal Cancer Growth through
miRNAs Regulation
1
,
,2,†
, Yurui Ma , Yifan Lin , Jiajie Liu , Rui Chen , Bin Xu 1,3,* and
2,†
1
1
2
Haoyu Wang
2
Yajun Liang *
1
Department of Chemistry, Qianweichang College, Shanghai University, Shanghai 200444, China;
hughie@shu.edu.cn (H.W.); miaomiao3327@126.com (Y.L.); ejay030201@163.com (J.L.)
School of Life Science, Shanghai University, Shanghai 200444, China; Myr819374294@163.com (Y.M.);
rchen94@hotmail.com (R.C.)
Innovative Drug Research Center, Shanghai University, Shanghai 200444, China
Correspondence: xubin@shu.edu.cn (B.X.); yajunl2017@126.com (Y.L.); Fax: +86-21-66132830 (B.X.)
These two authors contributed equally to this work.
2
3
*
†
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Yasuyoshi Miyata
Received: 12 June 2019; Accepted: 25 June 2019; Published: 25 June 2019
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Isoxazoline
and isoxazole derivatives represent an important class of five-membered heterocycles, which play a
pivotal role in drug discovery. In our previous study, we developed a series of isoxazole derivatives
with an efficient method. In this study, we evaluated their effects on tumor cell growth. HCT116
cells were treated with isoxazole derivatives; an cholecystokinin octapeptide (CCK-8) assay was
used to calculate the IC50 (half maximal inhibitory concentration) of each derivative. Compound
SHU00238, which was obtained by the copper nitrate-mediated [2+2+1] cycloaddition reaction of
olefinic azlactone with naphthalene-1,4-dione, has a lower IC ; we analyzed its inhibitory activity
50
in further assays. Cell apoptosis was estimated by flow cytometry analysis in vitro. SHU00238
injection was used to treat tumor-bearing mice. We found that SHU00238 suppressed cell viability
and promoted cell apoptosis in vitro. SHU00238 treatment significantly inhibited colonic tumor
growth in vivo. Furthermore, we compared the miRNAs expression changes in HCT116 cells before
and after SHU00238 treatment. MiRNA profiling revealed that SHU00238 treatment affected cell fate
by regulating a set of miRNAs. In conclusion, SHU00238 impedes CRC tumor cell proliferation and
promotes cell apoptosis by miRNAs regulation.
Keywords: colorectal cancer; isoxazole derivative; miRNAs; SHU00238; drug discovery
1
. Introduction
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide [
epigenetic alterations lead to the initiation of colorectal cancer. In addition, colorectal cancer is closely
related with lifestyle, age, and inflammatory disease [ ]. Most cases of colorectal cancer are sporadic
and slowly develop through adenoma-carcinoma sequences within a few years [ ]. The five-year
relative survival rate is greater than 90% in stage I patients. However, the survival rate is slightly above
0% in stage IV patients [ 10]. There is a critical need for the investigation of novel, molecular-targeted
therapeutics for CRC [11].
1]. Genetic and
2–6
7
1
8–
Isoxazole is a member of five-membered heterocycle; its adjacent position is composed of two
heteroatoms, an oxygen atom and a nitrogen atom [12]. The featured structure makes it easy to form
non-covalent interaction. Isoxazole compounds have a wide range of biological activities, including
Molecules 2019, 24, 2335; doi:10.3390/molecules24122335
www.mdpi.com/journal/molecules

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anti-cancer, anti-bacterial, anti-fungal, anti-viral, and anti-bacterial [13
–
15]. For instance, sulfisoxazole
has been applied in urinary tract infections and risperidone has been approved to treat schizophrenia in
adults [16]. In our previous study, we developed a novel, copper nitrate-mediated [2+2+1] cycloaddition
reaction and provided an alternative route for the expedient synthesis of pharmacologically interesting
3-aryl substituted isoxazolines and isoxazoles [17]. With this method, we synthesized a series of
isoxazole derivatives. In the present study, we determined their anti-tumor activities.
MicroRNAs (miRNAs, miRs) are ~21–23-nucleotide, single-stranded RNAs that play tremendous
regulatory roles in many biological processes; their dysregulation contributes to many diseases,
0
including cancer [18
of genes [21
–
20]. MiRNAs regulate gene expression via binding to the 3 -untranslated region
,
22]. Approximately two-thirds of protein-coding genes are regulated by miRNAs [23].
In this study, we synthesized 37 isoxazoline and isoxazole derivatives and determined their inhibitory
activities in HCT116 cells. Among them, SHU00238 inhibited CRC cell viability more efficiently;
Supplementary Material provides the preparation and spectroscopic data of SHU00238. In vitro and
in vivo data revealed that SHU00238 suppressed CRC growth. Furthermore, we performed miRNA
profiling with HCT116 cells treated with SHU00238. The data revealed that a set of miRNAs are
significantly regulated by SHU00238, which regulated cell fate by targeting several cellular signaling
pathways. Among the regulated miRNAs, miR-297, miR-30e-3p, miR-181d-5p, and miR-9-3p are
known tumor regulators [24–29]. Therefore, the present study reveals that SHU00238 suppresses
colorectal cancer growth through miRNAs regulation.
2
. Results
2
.1. An Isoxazole Derivative SHU00238 has a Lower IC50 in HCT116 Cells
The chemical structure of 37 candidate compounds is seen in Figure 1. We examined their
inhibitory activities in HCT116 cells. Preliminary data showed that SHU00238, SHU00240, SHU00242,
SHU00250, SHU00396, SHU03173, and SHU03174 could prohibit colonic tumor cells growth, as seen in
Figure 2A. Furthermore, we determined the IC50 of these compounds with CCK-8 assay. The results
showed that SHU00238 inhibited HCT116 cell viability with a lower IC50 value of 0.3552 µM, as seen
in Figure 2B. When we detected the cell apoptosis by AnnexV and PI (propidium iodide) staining, we
found that SHU00238 treatment promoted cell apoptosis prominently, as seen in Figure 2C.
2
.2. SHU00238 Suppresses Colonic Tumor Growth and Cell Proliferation in Xenograft Mice Model.
We explored the therapeutic effects of SHU00238 in tumor-bearing mice. HCT116 cells were
injected subcutaneously in nude mice and SHU00238 administration was performed when the tumor
3
size reached 500 mm . Results showed that SHU00238 significantly reduced xenograft tumor volume,
as seen in Figure 3A,B. In addition, we detected the expression of proliferation biomarkers in tumor
tissues with immunohistochemical analysis. Ki67 and PCNA (Proliferating cell nuclear antigen)
staining revealed that tumor cell proliferation was prominently reduced after SHU00238 treatment, as
seen in Figure 3C.

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Figure 1. Chemical structure of 37 candidate compounds.

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Figure 2. Seven compounds of 37 isoxazole derivatives suppress cell viability. (
of HT116 cells treated with 30 M isoxazole derivatives, as determined by CCK-8 assay. (
value of seven effective compounds in HCT116 cells, as determined by CCK-8 assay. ( ) Apoptosis
analysis of HCT116 cells treated with 0.3 µM, 1 µM SHU00238 (48 h, n = 3). ***, p < 0.001.
A
) Cell viability analysis
µ
B
) The IC50
C

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Figure 3. SHU00238 suppresses colonic tumor growth and cell proliferation in the xenograft mice
model. ( ) Tumor volume of control and SHU00238-treated mice (40 mg/kg, n = 9). ( ) Tumors of
) Ki67 and PCNA positive cells in
A
B
control and SHU00238-treated mice at the end of experiment. (
C
tumor tissues. Scale bar, 200 µM, *, p < 0.05.
2
.3. SHU00238 Treatment Affects Cell Fate by Regulating a Set of miRNAs
To investigate the underlying mechanism of SHU00238 in tumor suppression, we performed
miRNA microarray with HCT116 cells. A bioinformatics analysis revealed that SHU00238 treatment
significantly changed miRNA expression. Among these miRNAs, the known tumor regulators were
marked with underlines, as seen in Figure 4A. MiR-9-3p was identified as the tumor-suppressor
miRNA and performed its functions by targeting TAZ expression in liver cancer [28]. MiR-181a-5p
prevents cancer metastasis by targeting MMP-14 [27]. A blockade of miR-193a-5p increases the
chemosensitivity of prostate cancer cells to docetaxel. MiR-30e-3p functions as a tumor suppressor

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through targeting Snail1 in clear cell renal cell carcinoma [29]. To explore the regulation of SHU00238 to
cell fate, we analyzed the downstream genes of the regulated miRNAs, as seen in Figure 4B. GO(Gene
Ontology) enrichment and KEGG(Kyoto Encyclopedia of Genes and Genomes) analysis revealed that
cell fate-related signaling pathways were significantly changed by SHU00238 treatment, as seen in
Figure 4C,D. Overall, our study demonstrates that SHU00238 suppresses colonic tumor growth in vitro
and in vivo. SHU00238 affects cell fate by regulating a set of miRNAs.
Figure 4. SHU00238 treatment affects cell fate by regulating a set of miRNAs. (
the differential miRNAs. ( ) Target genes of differentially expressed miRNAs from the intersection
predicted with three databases (Targetscan, PITA, microRNAorg). ( ) GO analysis and ( ) KEGG
A) Heatmap of
B
C
D
analysis of the target genes. SHU00238 suppresses colonic tumor growth and cell proliferation in
xenograft mice model.
3
. Discussion
Isoxazole derivatives have a broad biological activities and play increasing important roles in drug
discovery [13 30]. In our previous study, we developed an efficient route for the expedient synthesis of
,

Molecules 2019, 24, 2335
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pharmacologically interesting 3-aryl substituted isoxazolines and isoxazoles [17]. In the present study,
we determined their inhibitory activity in colonic cancer cells. Among them, SHU00238, SHU00240,
SHU00242, SHU00250, SHU00396, SHU03173, and SHU03174, which all share a similarly featured
structure, prevent tumor cell viability efficiently. The compound SHU00238 has a lower IC50 value in
HCT116 cells, indicating its promising effects in tumor suppression.
Further analysis demonstrated that SHU00238 treatment promotes cell apoptosis in vitro. When
we treated tumor-bearing mice with SHU00238, tumor volume and colonic tumor cell proliferation
significantly decreased. Taken together, SHU00238 can inhibit colonic tumor growth both in vitro
and in vivo, which indicates therapeutic application in tumor therapy. However, cancer is a complex
disease; extensive studies are needed to determine the safety and metabolism of SHU00238 in tumor
suppression [31].
To investigate the underlying mechanism of SHU00238 in tumor suppression, miRNAs profiling
was performed [32–34]. Several known tumor regulators are significantly regulated by SHU00238
treatment. The functions of the other miRNAs in tumor progression are still to be elucidated. GO
enrichment and KEGG analysis revealed that SHU00238 might affect cell fate by regulating several
signaling pathways, such as Rap1 signaling pathway, Ras signaling pathway, MAPK signaling pathway,
AMPK signaling pathway, pathways in cancer, and PI3K-Akt signaling pathway. However, further
studies are needed to explain the mechanisms of SHU00238 treatment in tumor progression. Target
screen works still need to be elucidated because isoxazoles are facilitate to form non-covalent interaction
with other molecules.
4
. Materials and Methods
4
.1. Cell Culture
Colorectal cancer cell HCT116 is a human colon cancer cell line. HCT116 was bought from the
Chinese Academy of Sciences Cell Bank. Cells was cultured in Dulbecco’s modified Eagle’s medium
(
DMEM, Corning, New York, NY, USA) with 10% fetal bovine serum (FBS, CellMax, Shanghai, China)
◦
and 1% penicillin-streptomycin (PS, Gibco) at 37 C with 5% CO .
2
4
.2. Cell Viability Assay
Cell viability was detected with cholecystokini ocatapeptide (CCK-8) kit (Bioworld, Shanghai, China).
5
HCT116 cells were plated in 96-well plate at 2
×
10 /mL; cells were then treated with gradient-diluted
◦
compounds for 24 h. Cells were incubated with CCK-8 at 37 C for 1 h; we then measured the optical
density values (OD) 450 with microplate reader (Bio-Rad, Hercules, CA, USA). The IC50 of each compound
was calculated using SPSS software by logit-transformed probit model.
4
.3. Cell Apoptosis Assay
AnnexinV and PI Assay Kit (Beyotime, Shanghai, China) was used to measure the apoptosis level
of HCT116 cells. Briefly, HCT116 cells were treated with DMSO or compound. After 24 h, cells were
◦
resuspended in 100
µ
L PBS. Cells were stained with Annexin V and PI at 4 C for 20 min and then
these samples were detected with flow cytometry (Beckman, Brea, CA, USA).
4
.4. Tissue Immunohistochemistry
Xenograft tumor tissues were embedded in paraffin and sliced into 5
were incubated in 65 C for 2 h and then were dewaxed and dehydrated. Samples were boiled for
µ
m sections. Samples
◦
1
0 min to unmask antigens. Next, samples were immersed in 0.3% H O for 10 min to destruct the
2 2
endogenous peroxidase activity. We subsequently blocked the sections with 5% BSA, added 50 µL
primary antibodies against Ki67 (Abcam, 1:300, v/v, dilution) or PCNA (Proteintech, 1:300, v/v, dilution),
◦
and incubated overnight at 4 C. Secondary antibodies were added for 1 h at room temperature. Next,

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3,3-diaminobenzidine tetrahydrochloride (DAB) solution was used to amplify the signals. A total of
1
5 fields were randomly selected for each section under the microscope.
4
.5. Microarray Hybridization and Data Analysis
Two group of total RNA from HCT116 with or without SHU00238 treatment were subjected to
hybridization to Affymetrix miRNA4.0 arrays, performed by Shanghai OE Biotechnology Corporation.
The microarray data was normalized according to the median intensity of each sample. Differentially
expressed miRNAs were then identified through fold change as well as p-value calculated using a t-test.
The threshold set for up- and down-regulated genes was a fold change >= 2.0 and a p-value <= 0.05.
The miRNA array data have been deposited in GEO database. The accession number is GSE 132619.
4
.6. Mice and Treatment
Athymic nude mice were purchased from the Cavens lab (Changzhou, China). All animal
experiments were conducted according to institutional guidelines. Tumor-bearing mice were generated
6
by injecting 3
(
×
10 HCT116 cells subcutaneously in eight-week-old mice. Two weeks later, compound
50 mM, 1:5 dilution, 40 µL) was injected intraperitoneally every other day. Xenograft tumors were
dissected after 14 days. Tumor samples were fixed in 4% PFA and stored in liquid nitrogen for later
use. The protocol for this study was approved by the Animal Experiments Ethics Committee of School
of Life Science in Shanghai University. All surgical procedures were performed under isoflurane
anesthesia, and all efforts were made to minimize animal suffering and to reduce the number of
animals used.
4
.7. Statistical Analysis
All data were expressed as mean
Armonk, NY, USA) SPSS Statistics 20 and variables between groups were subject to either independent
±
SED. All statistical analyses were performed through IBM
(
sample; a t-test was used for comparisons between two groups. One-way analysis of variance (ANOVA)
was used for multiple comparisons. p-Values less than 0.05 were considered statistically significant.
Supplementary Materials: The following are available online.
Author Contributions: Conceptualization, B.X. and Y.L. (Yajun Liang); Formal analysis, Y.M., Y.L. (Yifan Lin) and
J.L.; Project administration and formal analysis, H.W. and R.C.
Funding: This work was funded by the grants from National Natural Science Foundation of China (81800265
to Y. Liang, 21871174 to B. Xu) and Innovation Program of Shanghai Municipal Education Commission
(No. 2019-01-07-00-09-E00008 to B. Xu).
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compound SHU00238 are available from the authors.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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