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Acta Biochim Biophys Sin, 2017, 1–7
doi: 10.1093/abbs/gmx107
Original Article
Original Article
Effects of high-intensity focused ultrasound on
cisplatin-resistant human lung adenocarcinoma
in vitro and in vivo
Tao Zhang1, Libin Chen2, Shengmin Zhang2, Youfeng Xu2,*, Yabo Fan1,
and Lizhong Zhang1
1
Department of Ultrasound, Ningbo No. 9 Hospital, Ningbo 315020, China, and 2Department of Ultrasound, Ningbo
First Hospital, Ningbo 315010, China
*Correspondence address. Tel/Fax: +86-574-87085004; E-mail: 2371334413@qq.com
Received 7 April 2017; Editorial Decision 27 June 2017
Abstract
It is widely accepted that high-intensity focused ultrasound (HIFU) is a minimally invasive treatment
option for different tumors, but its roles and the corresponding mechanism in cisplatin (DDP) chemoresistance in lung adenocarcinoma (LA) remain unclear. In this study, we investigated the
response of DDP-resistant LA cells to HIFU and its underlying molecular mechanisms using molecular biology techniques. It was found that HIFU exposure inhibited the proliferation of DDP-resistant
A549 (A549/DDP) cells through arresting cell cycle at the G1/G0 phase via the Cyclin-dependent pathway and promoting apoptosis in a Bcl-2-dependent manner. Furthermore, the results also showed
that HIFU exposure could down-regulate the expressions of MDR1, MRP1, and LRP mRNAs, as well
as P-gp, MRP1, and LRP proteins related to drug resistance in A549/DDP cells. In vivo experiments
also demonstrated that HIFU could reduce the size and mass of subcutaneously transplanted tumors
produced by A549/DDP cells through mediating Cyclin-dependent and Bcl-2-dependent pathways.
These results suggested that HIFU treatment could inhibit the proliferation of DDP-resistant lung
cancer cells and might be a novel therapeutic method for patients with DDP resistance.
Key words: high-intensity focused ultrasound, A549/DDP cells, growth inhibition, chemoresistance
Introduction
Lung cancer is the most commonly diagnosed tumor and ranks the first
for cancer-related death globally [1], of which the lung adenocarcinoma
(LA) accounts for more than 30% of all patients with lung cancer [2].
Currently, complete lung resection is the most effective therapy for LA,
but it is not suitable for patients diagnosed at advanced stage. Cisplatin
[cis-diamminedichloroplatinum (II); Pt(NH3)2Cl2; DDP]-based chemotherapy is based on the formation of DDP–DNA that leads to DNA
damage and sequentially activates the apoptosis signaling pathways in
cells, which is the first-line therapy for patients with advanced LA [3,4].
However, the development of DDP resistance often occurs in clinical
practice and is considered as a major obstacle limiting the success of
treatment [5,6]. Therefore, there is an urgent clinical need to seek adjuvant therapy which is effective for DDP-resistant LA cells.
High-intensity focused ultrasound (HIFU) is an emerging therapeutic technique that uses ultrasonic waves to induce protein degeneration and coagulation necrosis of tumor tissues by efficiently
targeting tumor entities [7]. In the past decade, HIFU has been
shown to treat different solid tumors without harming the surrounding tissues. In pancreatic cancer, several clinical studies have demonstrated that HIFU is a promising method for local tumor control
and palliative pain control [8–10]. Moreover, combination of HIFU
and gemcitabine has achieved even better therapeutic outcomes in
advanced pancreatic cancer patients [11,12]. In breast cancer, HIFU
treatment obviously decreased the expressions of proliferating cell
nuclear antigen (PCNA), cell adhesion molecule CD44v6 and
MMP-9 [13]. In addition, HIFU could enhance chemotherapeutic
drug delivery into tumor tissue by permeabilizing cell outer
© The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese
Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
1
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membrane [14]. HIFU ablation combined with DDP was found to
reduce tumor volume and increase tumor necrosis of cervical cancer
and bladder cancer [15,16]. However, the response of chemoresistant cells to insonation usually differs from that of chemosensitive
cells, which might be ascribed to multiple mechanisms underlying
the enhancement of DDP with ultrasound [17–19]. Recently, a study
showed that HIFU could inhibit human LA cell proliferation and
induce cell apoptosis [20]. However, the effect of HIFU on DDPresistant lung cancer cells and its corresponding mechanism have
not been revealed.
In this study, we investigated the response of DDP-resistant LA to
HIFU and its underlying molecular mechanisms using molecular biology techniques both in vitro and in vivo, which may help to develop
physical approaches that would resensitize the DDP-resistant cancer
cells to chemotherapy. The combination of therapeutic HIFU with chemotherapeutic agents might be used as a targeted tool for optimal
therapeutic efficacy.
Materials and Methods
Construction of DDP-resistant LA (A549/DDP) cell line
The human parent LA A549 cell line was obtained from the
Institute of Biochemistry and Cell Biology, Shanghai Institutes for
Biological Sciences (Shanghai, China). The DDP-resistant A549
(A549/DDP) cell line was established in our lab by addition of
increasing concentrations of DDP to the parent A549 cell culture
according to the procedures reported previously [21]. Both cell lines
were cultured in RPMI 1640 medium (GIBCO-BRL, Rockville,
USA) supplemented with 10% fetal bovine serum, 100 U/ml penicillin and 100 μg/ml streptomycin at 37°C in humidified atmosphere
containing 5% CO2.
Effects of HIFU on cisplatin chemoresistance
Shanghai, China). The number of colonies was observed and
counted under the CKX41 microscope (Olympus, Tokyo, Japan).
Flow cytometric analysis of cell cycle and apoptosis
For cell cycle analysis, cells were washed with ice-cold PBS, fixed
with 70% (v/v) ethanol overnight at −20°C and rehydrated in PBS
for 10 min. Then cells were stained with PI/RNase and subject to
flow cytometric analysis using a FACS instrument (Becton
Dickinson, Mountain View, USA) and CellQuest software (Becton
Dickinson). For apoptosis analysis, cells were harvested and fixed
with 2.5% (v/v) glutaraldehyde for 30 min. The rate of apoptosis
was determined using Annexin V-/7-AAD staining by flow
cytometry.
Quantitative real-time RT-PCR (qRT-PCR) analysis
Total RNA was extracted from either control or HIFU group cells
using TRIzol reagent (Invitrogen, Carlsbad, USA) and reversely transcribed to cDNA by M-MLV reverse transcriptase (Promega Corp.,
Madison, USA) according to the manufacturer’s instructions. The
qRT-PCR products were detected using SYBR Green PCR core
reagents in a BioRad Connet Real-Time PCR platform (Bio-Rad,
Hercules, USA). The primer sequences used were as follows: MDR1
(forward: 5′-GGAGCGGTTCTACGA-3′, and reverse: 5′-ACGAT
GCCCAGGTGT-3′); LRP (forward: 5′-AGTCAGAAGCCGAG
AAAG-3′, and reverse: 5′-CCCAGCCACAGCAAGGT-3′); MRP1
(forward: 5′-GTCGGAACAAGTCGTGCCTG-3′, and reverse: 5′-CAAA
GCCTCCACCTCCTCA-3′); and β-actin (forward: 5′-AAGGCTG
TGGGCAAGG-3′, and reverse: 5′-TGGAGGAGTGGGTGTCG-3′).
β-Actin was used as an internal reference control. The relative quantification of these mRNA levels was performed using the 2–ΔΔCt
method.
HIFU device and exposure
Western blot analysis
The prototype of a therapeutic HIFU system used in this study was
provided by Chongqing Haifu Technology Co., Ltd (Chongqing,
China). A total of 1,000,000 A549/DDP cells were placed in the test
tube and exposed to HIFU at the frequency of 1.048 MHz and the
intensity of 1000 W/cm2 for 9 s [22], which was defined as HIFU
group. The control group (Ctrl) samples were sham-exposed to
HIFU in the same fashion. After HIFU treatment, the cells were
incubated in a humidified atmosphere for 6 h, and then underwent
cell functional experiments, including cell viability, colony formation, cell cycle, and apoptosis assays. Each group consisted of at
least three experiments for the calculation of the mean values.
MTT assay was used to determine cell viability. Briefly, cells were
seeded into 96-well plates (2.0 × 103 cells/well) and allowed to
attach overnight. Then cells were mixed with 0.5 mg/ml MTT solution (Sigma, St Louis, USA). After 4 h of incubation, 150 μl of
dimethyl sulfoxide (DMSO) was added into each well to stop the
reaction. The absorbance in each well was measured at 595 nm
using a microplate reader (BioTek, Vermont, USA).
Cells or tumor tissues were lysed with protein extraction reagent
RIPA (Beyotime) with a protease inhibitor cocktail (Roche, Basel,
Switzerland). The cell lysates were centrifuged at 14,000 g for 15 min
to remove the cellular debris, and protein concentrations were determined by the Bradford methods. Approximately 50 μg of proteins
were separated by 10% SDS-PAGE and then transferred to PVDF
membrane (Amersham, Buckinghamshire, UK). The membranes were
blocked with 40 ml skimmed milk for 12 h and incubated with polyclonal antibodies against CDK2 (1:1000, #2546; Cell Signaling),
CDK4 (1:1000, 11026-2-AP; Proteintech), Cyclin D1 (1:1000, 601861-1g; Proteintech), Cyclin E (1:500, #21540; SAB), cleaved caspase-3
(1:500, #9661; Cell Signaling), cleaved PARP (1:1000, #9542; Cell
Signaling), Bcl-2 (1:1000, #9645; Cell Signaling), Bax (1:1000,
#8345; Cell Signaling), P-gp (1:1000, #4587; SAB), LRP (1:1000,
#23145; SAB) and MRP1 (1:1000, #9212; SAB) at 4°C overnight.
After 4 times of wash (15 min), the membranes were incubated with
the corresponding horseradish peroxidase (HRP)-conjugated secondary antibodies (1:500,000, 10494-1-AP; Proteintech) for 2 h at room
temperature. GAPDH antibody was used as a control. Protein bands
were finally visualized using super ECL detection reagent (Pierce Inc.,
Rockford, USA).
Colony formation assay
Animal experiments
Cells were seeded in 6-well plates at 500 cells/well after being trypsinized into single cell suspension. After 7 days of culture, the colonies
formed were stained with 500 μl crystal violet solution (Beyotime,
Six-week-old BALB/c nude mice were purchased from Shanghai Slac
Laboratory Animal Co., Ltd (Shanghai, China). A549/DDP cells
were exposed to HIFU but control samples were sham-exposed
Cell viability assay
3
Effects of HIFU on cisplatin chemoresistance
(Ctrl) in the same fashion. HIFU exposure parameters used in this
study were 1.048 MHz and 1000 W/cm2 for 9 s.
To produce tumor, HIFU-treated A549/DDP cells (1.0 × 107
cells) were injected subcutaneously into the three mice using a 1 ml
needle, respectively. Untreated A549/DDP cells (Ctrl) in same number were inoculated into three mice as control. The animals inoculated with cancer cells were raised routinely, with free access to food
and water. The size of solid tumor was measured with a caliper
every 3 days for 27 days. Mice were sacrificed 27 days after treatment. The experiments on mice had been approved by the Ethics
Committee at Ningbo First Hospital.
Results
Establishment of DDP-resistant LA (A549/DDP) cell line
To investigate the acquired resistance of LA cells to DDP, we constructed an A549/DDP subline from the parent A549 cells and performed a series of validation experiments. As shown in Fig. 1, parent
A549 cells showed lower cell viability than A549/DDP cells under the
same concentration of DDP as revealed by MTT assay, suggesting that
A549 cells presented higher sensitivity to DDP treatment than A549/
DDP cells. The IC50 value of DDP in parent A549 cells was 18.54 ±
1.74 μg/ml, which was significantly lower than that in A549/DDP cells
(34.13 ± 2.14 μg/ml; P < 0.01). This result indicated that a stable
DDP-resistant cell line (A549/DDP) was successfully established.
Statistical analysis
Data were presented as the mean ± SD from at least three experiments. The statistical difference between the mean values of two
groups was evaluated by Student’s t-test using SPSS software (version
13.0). The significance level was set at a P value of less than 0.05.
HIFU inhibited the proliferation of DDP-resistant LA
(A549/DDP) cells
To investigate the roles of HIFU in the A549/DDP cells, we first
determined the cell viability of A549/DDP cells after HIFU treatment
Figure 1. Characterization of DDP-resistant human LA (A549/DDP) cells Cell viability was determined by MTT assay in A549 and A549/DDP cells after treatment with increasing concentrations of DDP for 24 h. The IC50 values of DDP to A549/DDP and A549 cells were calculated, respectively. **P < 0.01.
Figure 2. Effect of HIFU on DDP-resistant human LA (A549/DDP) cells (A) Cell viability was determined by MTT assay before and after exposure to HIFU at 0,
24, 48, 72 and 96 h. (B) Representative photographs of single colony and total colonies in plates were shown in control and HIFU-exposed cells by crystal violet
staining. (C) The average number of colonies in control and HIFU-exposed cells was shown. Data are expressed as the mean ± SD of three independent experiments. Ctrl represents A549/DDP cells. HIFU represents A549/DDP cells exposed to HIFU. **P < 0.01, ***P < 0.001.
4
by MTT assay. As shown in Fig. 2A, HIFU exposure significantly
inhibited the cell viability of A549/DDP cells (P < 0.01). Then the
effect of HIFU on colony formation ability of A549/DDP cells was
evaluated. Compared with the control cells, the number of colonies
formed by HIFU-exposed cells was apparently reduced (Fig. 2B,C,
P < 0.001). These results indicated that HIFU could significantly
inhibit the cell viability and capacity of colony formation in A549/
DDP cells.
HIFU inhibited the proliferation of DDP-resistant LA
(A549/DDP) cells by inducing cell cycle arrest in G0/G1
phase
Then, the effects of HIFU on cell cycle of A549/DDP cells were analyzed by flow cytometry (Fig. 3A). Compared with the control
A549/DDP cells, the percentage of HIFU-exposed A549/DDP cells
in G0/G1 phase of cell cycle was significantly increased and the percentage of cells in S phase was notably decreased (Fig. 3B, P < 0.05,
P < 0.001). In addition, the expressions of CDK2, CDK4, Cyclin
D1, and Cyclin E proteins were significantly downregulated in
HIFU-exposed A549/DDP cells compared with those in the control
A549/DDP cells (Fig. 3C). These results suggested that HIFU might
reverse the DDP resistance of A549/DDP cells by partially inducing
G0/G1 phase cell arrest.
Effects of HIFU on cisplatin chemoresistance
HIFU inhibited the proliferation of DDP-resistant LA
(A549/DDP) cells by promoting cell apoptosis
Next, the apoptosis of the control A549/DDP cells and HIFUexposed A549/DDP cells was determined by flow cytometry
(Fig. 4A). The results showed that the early apoptotic rate was significantly increased from 4.41% in the control A549/DDP cells to
13.51% in the HIFU-exposed A549/DDP cells. Similarly, the late
apoptotic rate was also increased in the HIFU-exposed A549/DDP
cells compared with the control A549/DDP cells (Fig. 4B, P <
0.001). Furthermore, HIFU exposure obviously increased the
expressions of cleaved caspase-3 and PARP, and decreased the
expression of Bcl-2 (Fig. 4C). These results indicated that HIFU
inhibited A549/DDP cell proliferation by partially promoting cell
apoptosis.
HIFU downregulated the expression of drug resistanceassociated molecules in DDP-resistant LA (A549/DDP)
cells
To gain further insight into the mechanisms related to the effects of
HIFU exposure on A549/DDP cells, we investigated the effect of HIFU
on the expression of P-gp/MDR1, LRP and MRP1 using qRT-PCR and
western blot analysis. As shown in Fig. 5A–C, HIFU could significantly
suppress the expressions of MDR1, LRP and MRP1 mRNAs in A549/
Figure 3. Effect of HIFU on cell cycle distribution in DDP-resistant human LA (A549/DDP) cells (A) Cell cycle distribution of control and HIFU-exposed cells was
analyzed by flow cytometry. (B) Statistical analysis of the percentage of control and HIFU-exposed cells in G0/G1, S, and G2/M phase, respectively. (C) The
expression of CDK2, CDK4, Cyclin D1, and Cyclin E in control and HIFU-exposed cells by western blot analysis. Data are expressed as the mean ± SD of three
independent experiments. Ctrl represents A549/DDP cells without exposure to HIFU. HIFU represents A549/DDP cells exposed to HIFU. *P < 0.05, ***P < 0.001.
Effects of HIFU on cisplatin chemoresistance
5
Figure 4. Effect of HIFU on cell apoptosis in DDP-resistant human LA (A549/DDP) cells (A) Flow cytometric analysis of apoptosis in control and HIFU-exposed
cells. (B) Statistical analysis of early apoptosis and late apoptosis in control and HIFU-exposed cells. (C) The expressions of cleaved caspase-3, PARP, and Bcl-2
in control and HIFU-exposed cells by western blot analysis. Ctrl represents A549/DDP cells without exposure to HIFU. HIFU represents A549/DDP cells exposed
to HIFU. Data are expressed as the mean ± SD of three independent experiments. ***P < 0.001.
Figure 5. Effect of HIFU on drug resistance-associated expression in DDP-resistant human LA (A549/DDP) cells The mRNA and protein expression of P-gp/
MDR1 (A), LRP (B), and MRP1 (C) was determined by qRT-PCR and western blot analysis. β-Actin and GAPDH were used as internal controls. Data are expressed
as the mean ± SD of three independent experiments. Ctrl represents A549/DDP cells without exposure to HIFU. HIFU represents A549/DDP cells exposed to
HIFU. *P < 0.05 or **P < 0.01.
DDP cells at transcription level. Consistently, the expression of P-gp,
LRP and MRP1 proteins was obviously decreased in HIFU-exposed
A549/DDP cells compared with the control A549/DDP cells.
HIFU inhibited tumor growth derived from DDPresistant LA (A549/DDP) cells in vivo
To further verify the effect of HIFU on DDP resistance in vivo, we
inoculated control A549/DDP cells and HIFU-exposed A549/DDP
cells into the nude mice to developed tumor. As shown in Fig. 6A,B,
tumor in the HIFU group grew much slower than tumor in the control group. At the end of the study, on Day 27, tumor weight of the
HIFU group (0.6 ± 0.16 g) was only 34.5% of that of the control
group (1.74 ± 0.06 g) (Fig. 6C). Compared with control group,
HIFU treatment significantly decreased tumor weight (P < 0.001). To
correlate the biological response with the mechanisms identified in
tumor tissues, the expressions of CDK4, Cyclin D1, Bax and MRP1
proteins were determined by western blot analysis. Consistent with
the in vitro results, the expression levels of CDK4, Cyclin D1, and
MRP1 were downregulated, but Bax was upregulated in HIFU group
6
Effects of HIFU on cisplatin chemoresistance
Figure 6. Effect of HIFU on the tumor inducing ability of A549/DDP cells in vivo (A) Representative images of tumors from mice in Ctrl and HIFU groups. (B,C)
The volume and weight of tumors from mice in Ctrl and HIFU groups. (D) Western blot analysis of the expressions of CDK4, Cyclin D1, Bax, and MRP1 in Ctrl
and HIFU groups. Ctrl means the tumor was produced in mice by injection of A549/DDP cells without exposure to HIFU. HIFU group means the tumor was produced in mice by injection of A549/DDP cells treated with HIFU. *P < 0.05, ***P < 0.001.
compared with Ctrl group (Fig. 6D). These results indicated that
tumor growth formed from A549/DDP cells in vivo could be obviously inhibited after HIFU treatment.
Discussion
Recent studies have demonstrated that combined HIFU and chemotherapy can result in better outcomes, including high pain relief and
longer survival by improving total drug levels and distributions of
bioavailable drug [23–25]. However, the effects and corresponding
mechanisms of HIFU in DDP-resistance LA cells have not been
clearly identified. In the current study, we established DDP-resistant
A549/DDP cells to explore the effect of HIFU on DDP-resistant LA
cells in vitro and tumor growth in vivo.
DDP, a DNA damaging agent, has been used as a systematic chemotherapeutic agent for various human tumors including LA.
Unfortunately, some factors, including the reduced intracellular drug
accumulation, increased anti-apoptotic proteins and decreased proapoptotic proteins are involved in intrinsic or acquired tumor cell
resistance to DDP, leading to limited therapeutic efficacy [26–28].
HIFU, as a valuable tool for minimally invasive tumor ablation, has
been demonstrated to induce apoptosis by mediating p53 and Bcl-2
family [20]. In addition, HIFU could decrease the multidrug resistance through decreasing the expression of P-gp protein [29]. In our
results, HIFU exposure obviously decreased the chemoresistant ability of A549/DDP cells. Further analysis indicated that HIFU could
significantly inhibit A549/DDP cell proliferation by inducing cell
cycle G0/G1 phase arrest and apoptosis. The Cyclins and their partners (CDKs) play a well-established role in the regulation of the cell
cycle, of which CDK2-Cyclin E and Cyclin D-CDK4/CDK6 are
required for G0/S transition [30,31]. We found that the expressions
of CDK2, CDK4, Cyclin D1, and Cyclin E were remarkably
decreased by HIFU treatment in A549/DDP cells. Furthermore, HIFU
exposure significantly enhanced the expressions of pro-apoptotic proteins, cleaved caspase-3 and PARP, and decreased the expression of
anti-apoptotic protein Bcl-2. A similar result was also observed
in vivo. These results may provide evidence that ultrasound plays an
ever-increasing role in the delivery of therapeutic chemotherapeutic
agents [14].
In addition, we investigated the effect of HIFU on the expression
of resistance-related proteins. We found that HIFU decreased P-gp,
MRP1, and LRP expressions at both mRNA and protein levels
in vitro and in vivo. Related research suggests that the reversal of
cancer drug resistance in clinical trials is mainly ascribed to several
factors, such as low binding affinity, the inhibition of metabolism
and the excretion of anticancer drugs [32]. Based on these facts, we
deduce that HIFU may inhibit DDP-resistant LA cell proliferation
possibly through down-regulating the expressions of resistancerelated molecules.
However, there are some limitations in this study. For example,
there is still lack of evidence that HIFU, as causation, could reverse
DDP resistance phenomenon in cancer cells. Despite the suppressive
effects of HIFU on DDP-resistant LA cells, difference still exists
between laboratory and clinical trials in the use of HIFU to sensitize
chemotherapy, as reported by Yu et al. [33].
In summary, our data demonstrated that HIFU exposure could
inhibit DDP-resistant LA cell proliferation via regulating G1/S transition and apoptosis, as well as by down-regulating the expressions
of drug resistance-associated molecules. To some degree, these findings will provide an experimental basis for HIFU as an adjuvant
therapy in patients with advanced stage lung cancer.
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