Synergistic anti-proliferative effects of combination of ABT-263 and MCL-1 selective inhibitor A-1210477 on cervical cancer cell lines
Lian et al. BMC Res Notes
Synergistic anti-proliferative effects of combination of ABT-263 and MCL-1 selective inhibitor A-1210477 on cervical cancer cell lines
Benedict Shi Xiang Lian 0 2
Angeline En Hui Yek 0 2
Hemalata Shuvas 0 2
Siti Fairus Abdul Rahman 0 2
Kalaivani Muniandy 1
Nethia Mohana‑Kumaran 0 2
0 School of Biological Sciences, Universiti Sains Malaysia , 11800 Gelugor, Penang , Malaysia
1 Institute for Molecular Medicine (INFORMM), Universiti Sains Malaysia , 11800 Gelugor, Penang , Malaysia
2 School of Biological Sciences, Universiti Sains Malaysia , 11800 Gelugor, Pen‐ ang , Malaysia
Objective: There are number of studies which report that BCL‑ 2 anti‑ apoptotic proteins (e.g. BCL‑ 2, BCL‑ XL, and MCL1) are highly expressed in cervical cancer tissues compared to the normal cervical epithelia. Despite these reports, targeting these proteins for cervical cancer treatment has not been explored extensively. BH3‑ mimetics that inhibit specific BCL‑ 2 anti‑ apoptotic proteins may hold encouraging treatment outcomes for cervical cancer management. Hence, the aim of this pilot study is to investigate the sensitivity of cervical cancer cell lines to combination of two BH3‑ mimetics namely ABT‑ 263 which selectively inhibits BCL‑ 2, BCL‑ XL and BCL‑ w and A‑ 1210477, a selective MCL‑ 1 inhibitor. Results: We report that combination of A‑ 1210477 and ABT‑ 263 exhibited synergistic effects on all cervical cancer cell lines tested. Drug sensitization studies revealed that A‑ 1210477 sensitised the cervical cancer cell lines SiHa and CaSki to ABT‑ 263 by 11‑ and fivefold, respectively. Sensitization also occurred in the opposite direction whereby ABT‑ 263 sensitised SiHa and CaSki to A‑ 1210477 by eightfold. This report shows that combination of ABT‑ 263 and A‑ 1210477 could be a potential treatment strategy for cervical cancer. Extensive drug mechanistic studies and drug sensitivity studies in physiological models are necessary to unleash the prospect of this combination for cervical cancer therapy.
Cervical cancer; BH3‑ mimetic; ABT‑ 263; A‑ 1210477
Cervical cancer is the third leading cause of cancer
death in females in less developed nations [
]. The cure
rate with existing treatment modalities is between 60
and 90% for women who are diagnosed early.
Unfortunately, prognosis is poor for women who are
diagnosed with advanced or recurrent cervical cancer. The
5-year survival for women with metastatic cancer is
only 16.5% [
]. Thus far, cisplatin and paclitaxel remain
as the most effective treatment and standard of care for
cervical cancer management. Several targeted therapies
were evaluated for treatment but only exhibited limited
]. Bevacizumab a recombinant and
humanized monoclonal antibody against vascular endothelial
growth factor (VEGF) is the only targeted therapy which
has demonstrated improved overall survival (3.7 months)
when combined with chemotherapy in a phase III study
The BCL-2 family proteins, divided into pro- and
antiapoptotic proteins are the regulators of the intrinsic
apoptosis pathway [
]. The anti-apoptotic BCL-2
proteins are up-regulated in many cancers and hence have
emerged as attractive targets for therapy especially with
the development of BH3-mimetics namely ABT-263
which specifically targets these proteins [
Numbers of studies have evaluated the expression of
the anti-apoptotic proteins at different stages of cervical
cancer using immunoblot, immunohistochemistry (IHC)
and oligonucleotide microarray profiling. Using IHC,
BCL-2 and tumour suppressor protein p53 was detected
to co-express in biopsies of cervical lesions but not in the
normal cervical epithelium [
]. Employing the same
technique, expression levels of survivin (inhibitor of
apoptosis), BCL-2 and KAI 1 (tumour metastases suppressor
protein) were investigated in normal cervix, chronic
cervicitis, cervical intraepithelial neoplasia (CIN) and
cervical cancer. Expression levels of survivin and BCL-2 were
higher in the cervical cancer tissues than in the normal
cervix, chronic cervicitis, or CIN and vice versa for KAI
1. Collectively, high expression of survivin and BCL-2
and low expression of KAI 1 were reported to promote
cervical cancer progression and metastasis [
study using IHC, demonstrated that expression of BCL-2
was the highest in the invasive squamous cell carcinoma
cervical tissues compared to normal cervical epithelium
and CIN tissues [
]. MCL-1 was found to be
overexpressed in cervical cancer tissues compared to its
normal counterpart and the overexpression was correlated
with poor prognosis. In this study IHC and immunoblot
yielded similar results, bolstering confidence in the
]. Collectively, these studies suggest that the
antiapoptotic proteins are relevant targets for cervical cancer
ABT-263 binds with high affinity to anti-apoptotic
proteins BCL-2 and BCL-XL and with lower affinity to
]. ABT-263 has demonstrated impressive
single agent activity against lymphoid malignancies and
small cell lung cancer (SCLC). Phase I/II trials report
that ABT-263 was either effective as a single agent 
or in combination with other drugs in refractory chronic
lymphocytic leukaemia (CLL) [
]. In most solid
tumours, it has become obvious that sensitivity to
ABT263 is determined by MCL-1, which the drug binds with
very low affinity. Suppression of MCL-1 or induction of
MCL-1 antagonist NOXA have shown to sensitize solid
cancer cells to ABT-263 [
]. In the present study,
we performed a preliminary study to investigate the
sensitivity of three cervical cancer cell lines namely SiHa,
CaSki, and C33A to combination of ABT-263
(Navitoclax, AbbVie Inc) , and MCL-1 selective inhibitor
A-1210477 (AbbVie, Inc) [
] using 2-dimensional drug
Cell lines and culture
SiHa was maintained in DMEM medium
supplemented with 10% (v/v) heat-inactivated foetal bovine
serum (FBS), 10 U/ml penicillin and 10 μg/ml
streptomycin, 1% (v/v) HEPES, 1 mM sodium pyruvate and
2 mM l-glutamine. C33A was maintained in DMEM
medium supplemented with 10% (v/v) heat-inactivated
FBS, 10 U/ml penicillin and 10 μg/ml streptomycin,
2 mM l-glutamine and 4.5 g/l d-Glucose, and CaSki was
maintained in RPMI medium supplemented with 10%
heat-inactivated FBS, 10 U/ml penicillin and 10 μg/ml
streptomycin. The human foreskin fibroblasts were
maintained in DMEM medium supplemented with 20% (v/v)
FBS, 1 mM sodium pyruvate and 2 mM l-glutamine. All
cell culture reagents were purchased from Gibco; Thermo
Fisher Scientific, Waltham, MA, USA. Cells were
incubated in 37 °C, 5% CO2. Unnecessary passaging of cell
lines was avoided; experiments were conducted within
two passages of reference stocks.
Two‑dimensional (2D) drug sensitivity assay
The 2D drug sensitivity assays were performed as
]. Cells were seeded at 2500 cells per
well in 96-well plates and left to attach for 6–7 h in a
humidified incubator at 37 °C, 5% CO2. After attachment,
cells were treated to a concentration series [0–32 μM]
of single agent ABT-263 and A-1210477 and as
combination along the long plate axis for 72 h. Similar drug
concentrations of ABT-263 and A-1210477 as previously
described by [
] were used in this study.
Sensitization to ABT-263 by A-1210477 was assessed by testing a
fixed concentration of A-1210477 to increasing
concentrations and ABT-263 and vice versa for 72 h. Cell
proliferation was quantified by fluorescence of SyBr Green
I nucleic acid stain (Molecular Probes, Thermo Fisher
Scientific, Waltham, MA, USA) employing a plate reader
with 485 nm excitation and 530 nm emission filters.
Comparisons of IC50 values of the combination with
either single agent A-1210477 or ABT-263 were done
by two-tailed paired T test using GraphPad Prism®
version 7 software. The values of p-values are indicated as
***p ≤ 0.001 or ****p ≤ 0.0001.
Drug interaction analyses
Synergistic drug interaction was determined using the
median effect principle as previously described by Chou
and Talalay [
]. The CompuSyn 1.0 software
(ComboSyn Inc. NJ, USA) was employed to generate Fa-CI
Synergistic anti‑proliferative effect of ABT‑263
and A‑1210477 in the cervical cancer cell lines
Despite number of studies reporting on high
expression of the anti-apoptotic proteins in cervical cancer
tissues, targeting these proteins for therapy received very
little attention. Here we conducted a preliminary study
to investigate the sensitivity of three cervical cancer cell
lines to BH3-mimetic ABT-263 which selectively
inhibits BCL-2, BCL-XL and BCL-w and A-1210477, a
selective MCL-1 inhibitor. The cells were tested to single agent
activity of ABT-263 and A-1210477 and as combination.
In order to determine that the drugs did have an effect on
cell proliferation of normal cells, the drugs were tested on
human foreskin fibroblasts (HFFs).
All three cervical cancer cell lines were resistant to
single agent activity of ABT-263 (SiHa IC50 11.13 ± 0.48 µM;
CaSki IC50 3.4 ± 0.13 µM; C33A IC50 11.77 ± 0.11 µM—
Fig. 1a–c—closed diamond) and A-1210477 ((SiHa IC50
20.23 ± 0.55 µM; CaSki IC50 6.7 ± 0.04 µM; C33A IC50
11.97 ± 0.22 µM—Fig. 1a–c—closed triangle).
Combination of ABT-263 and A-1210477 at 1:1 drug
concentration ratio shifted the dose–response curve to the left
exhibiting selective synergistic anti-proliferative effects in
all three cell lines (SiHa IC50 3.07 ± 0.11 µM; CaSki IC50
1.6 ± 0.04 µM; C33A IC50 3.11 ± 0.06 µM—Fig. 1a–c—
closed circle). The IC50 of the drug combination in the
HFFs was 8.1 ± 0.6 µM—Additional file 1—closed circle).
The IC50 concentration obtained for the combination in
the HFFs were higher compared to the cervical cancer
cell lines (Fig. 1a–c—closed circle) indicating that
inhibition of cell proliferation in cervical cancer cell lines
with combination of ABT-263 and A-1210477 could be
achieved at lower drug concentrations without
employing doses that could harm non-cancerous cells.
Sensitization of cervical cancer cell lines SiHa and CaSki
to ABT‑263 by A‑1210477 and vice versa
Next, we investigated the sensitization effect of one
drug by another in the SiHa and CaSki cells. We first
tested the sensitization effect of ABT-263 by A-1210477
by adding a fix concentration of 4 μM of A-1210477
to increasing doses of ABT-263. SiHa and CaSki were
resistant to single agent activity of ABT-263 (SiHa IC50
10.12 ± 0.34 µM; CaSki IC50 3.4 ± 0.13 µM – Fig. 2a,
b—closed diamond). The presence of A-1210477
shifted the dose–response curve to the left,
displaying the ability of A-1210477 to potentiate SiHa and
CaSki to ABT-263 (SiHa IC50 2 ± 0.15 µM; CaSki IC50
0.3 ± 0.0013 µM—Fig. 2a, b—closed triangle) by 5- and
11-fold, respectively (Table 1). Sensitization was also
studied in the opposite direction by adding a fix dose of
Sensitization of the cervical cancer cell lines to ABT-263 by A-1210477
4 µM A-1210477
The IC50 values are doses of drug 1 (bolditalics) that kill 50% of the cells surviving
the shown doses of drug 2 (italics). Fold sensitization IC50 drug 1/IC50 drug 2.
Errors are SEM, n = 4
Statistically significant differences with the IC50 of drug 1 (bolditalics) are shown
as *** p ≤ 0.001 or **** p ≤ 0.0001 determined by two-tailed paired T test. Where
the IC50 was not calculable, the lower bound was employed
ABT-263 (4 μM ABT-263 for SiHa and 2 μM ABT-263
for CaSki) to escalating doses of A-1210477. Both cells
were resistant to single agent activity of A-1210477
(SiHa IC50 19.86 ± 0.53 µM; CaSki IC50 7.6 ± 0.11 µM—
Fig. 2c, d—closed triangle). Combination with
ABT263 sensitized both cell lines to A-1210477 (SiHa IC50:
2.58 ± 0.2 µM; CaSki IC50 0.9 ± 0.13 µM—Fig. 2c, d—
closed diamond) by eightfold (Table 1). Combination
index (CI) values for all combinations tested are shown
in Table 1. Drug combination was synergistic at CI
value of less than 1 (Additional file 2).
Taken together our data demonstrated that the drug
combination synergistic anti-proliferative effects could
be explained by the ability of both drugs to sensitize
each other. Hence, ABT-263 and A-1210477 may be
effective sensitizers at physiologically attainable doses.
Neutralisation of MCL-1 is required for enhanced
anti-cancer efficacy of ABT-263. Hence tumours that
are normally unresponsive to ABT-263 may become
amenable to treatment when combined with drugs
which either repress MCL-1 or induce MCL-1
antagonist NOXA [
]. In our preliminary study, we aim to
investigate the sensitivity of cervical cancer cell lines to
ABT-263 when combined with MCL-1 selective
inhibitor A-1210477. Our findings showed that compared to
single agent treatment, combination of ABT-263 and
A-1210477 caused a synergistic anti-proliferative effect
in all three cell lines tested. The results obtained were
in accordance with other studies [
In order to fully unravel the potential of
combination of ABT-263 with its partner drug, we tested the
sensitization of the cervical cancer cell lines to
ABT263 by A-1210477 and vice versa. In our hands,
ABT263 sensitized cervical cancer cell lines SiHa and
CaSki to A-1210477 and vice versa demonstrating that
both drugs can augment the activity of each other and
restore the apoptotic potential in tumour cells. This was
in agreement with other studies which reported that
ABT-263 sensitized the effect of docetaxel in SKOV3
ovarian cancer xenograft model and erlotinib in the
NCI-H1650 NSCLC xenograft model [
study reported that ABT-263 enhanced the activity of
etoposide and Bortezomib in vivo [
A-1210477, similar to our findings, sensitized a
number of cell lines from different cancer types namely
BxPC-3 pancreas adenocarcinoma line, H23-lung
carcinoma line, EJ-1 gastric carcinoma line and OPM-2
multiple myeloma line to ABT-263 in vitro [
sensitization effect of A-1210477 was also obvious in
studies which used breast cancer [
non-Hodgkin’s lymphoma cell lines [
]. However, A-1210477
although highly specific for MCL-1, its ability to bind
to serum proteins may limit its bioavailability and this
could lead to drug resistance in preclinical models and
patients as sufficient amount may not reach the tumour
Taken together our data demonstrates that
combination of ABT-263 and A-1210477 exhibited synergistic
effects in all cervical cancer cell lines tested and both
drugs have the ability to enhance the activity of each
other at physiologically attainable concentrations.
Combination of these drugs could be a potential
therapy option to combat cervical cancer but further
studies are necessary to fully unleash the prospect of this
Sensitivity of the cervical cancer cell lines to
combination of ABT-263 and A-1210477 were performed in the
2D cell culture model. The 2D model is
high-throughput and economical but it lacks the
microenvironment that tumours encounter in vivo [
that A-1210477 may demonstrate poor bioavailability
in vivo, future studies in three-dimensional (3D)
spheroid models, in vivo models and later in clinical trials
should test combination of orally bioavailable ABT-263
with next generation MCL-1 inhibitors with improved
bioavailability properties . Future work should also
investigate the expression of the BCL-2 proteins and
caspases before and after treatment so that a
mechanism for induction of apoptosis in cervical cancer cell
lines by the drug combination could be established.
Additional file 1. Anti‑proliferative effects of ABT ‑263 and A‑1210477
in human foreskin fibroblasts at 1:1 drug concentration ratios. This data
shows the effect of the BH3 mimetic drug combination on cell viability of
a non‑ cancerous cell line.
Additional file 2. Synergistic drug effects of ABT‑263 and A‑1210477 in
the SiHa and CaSki cervical cancer cell lines. This data shows the drug
combination interaction effects in two cervical cancer cell lines.
VEGF: vascular endothelial growth factor; IHC: immunohistochemistry; CIN:
cervical intraepithelial neoplasia; SCLC: small cell lung cancer; CLL: chronic
lymphocytic leukaemia; 2D: 2‑ dimensional; HFF: human foreskin fibroblasts; CI:
combination index; 3D: 3‑ dimensional.
NM‑K designed the experiments and wrote the manuscript. BSXL, AEHA, HS,
SFAR, and KM performed the experiments, analysed, and interpreted the data.
NM‑K prepared the figures and tables. SFAR corrected and proofread the
manuscript. All authors read and approved the final manuscript.
We would like to thank AbbVie Inc for providing us with ABT‑263 and
A‑1210477. We thank Prof. Dr. Cheong Sok Ching from Cancer Research Malay‑
sia for providing us with the human foreskin fibroblasts and Prof. Dr. Nikolas
Haass (University of Queensland, Australia), Assoc. Prof. Dr. Nigel McMillan
(University of Griffith, Australia), and Assoc. Prof. Dr. Venugopal Balakrishnan
(INFORMM, USM) for providing us with the cervical cancer cell lines.
The authors declare that they have no competing interests.
Availability of data and materials
All data generated or analysed during this study are included in this published
article (and its additional files).
Consent for publication
Ethics approval and consent to participate
B.S.X. Lian and K. Muniandy are Universiti Sains Malaysia Fellowship recipi‑
ents. This work was funded by the Fundamental Research Grant Scheme,
Ministry of Higher Education Malaysia (203/PBIOLOGI/6711355 and 203/
PBIOLOGI/6711541), Universiti Sains Malaysia Short‑ Term Grant (304/PBI‑
OLOGI/6313312), and MAKNA Cancer Research Award 2015, National Cancer
Council, Malaysia (304/PBIOLOGI/650828/M121).
Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations.
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