CUDC-101 enhances the chemosensitivity of gemcitabine-treated
lymphoma cells
Hongyan Li a,1
, Rihua Cui a,1
, Meiying Ji b,
*, Sheng-Yu Jin a,b,
a Department of Hematology, Yanbian University Hospital, Jilin, Yanji, 133000, China b Research center of Yanbian University Hospital, Jilin, Yanji, 133000, China
Non-hodgkin’s lymphoma (NHL)
HDAC signal pathway
Background: The metastasis and recurrence of Non-Hodgkin’s lymphoma (NHL) is a major cause of morbidity and
mortality. Recent work suggests that drugs capable of targeting epigenetic regulatory mechanisms may be well
suited to the treatment of such disease progression.
Methods: This study was thus designed to evaluate the ability of the novel histone deacetylase (HDAC) inhibitor
CUDC-101 to synergize with gemcitabine in order to kill human HUT78 and Pfeiffer NHL cells. To that end, we
analyzed the viability of these NHL cells via CCK-8 assay, while the incidence of apoptosis among treated cells
was evaluated via Annexin V-FITC/PI staining and by the Western blotting-mediated evaluation of proteins
associate with apoptosis and related signaling pathways.
Results: We found that CUDC-101 and gemcitabine interacted synergistically to reduce NHL cell viability and to
induce the apoptotic death of these cells via the EGFR/ PI3K/Akt and Erk pathways, which were regulated by
HDAC signaling pathways.
Conclusion: Together, our results highlight the anti-cancer properties of CUDC-101 alone or in combination with
gemcitabine as an approach to inducing the apoptotic death of lymphoma cells in vitro, while also offering insight
into the underlying molecular mechanisms governing this activity.
1. Background
Non-Hodgkin’s lymphoma (NHL) is a heterogeneous form of
lymphatic malignancy, with most NHL cases originating from B cells and
with just 10 % of these cases being of the T cell lymphoma subtype [1].
NHL patients have traditionally been treated with the CHOP (cyclo￾phosphamide, doxorubicin, vincristine, and prednisolone) chemo￾therapy regimen [2]. While efficacious in some cases, many NHL
patients ultimately experience relapsed or refractory (R/R) disease,
which is associated with a 3-year overall survival rate of just 30 % [3].
Relapsed patients are typically treated with higher CHOP doses or with
additional anti-cancer drugs, but higher CHOP dosages are only effective
in one-third of relapsed NHL patients, and are associated with serious
side-effects [4]. It is therefore essential that novel treatments associated
with higher rates of curative efficacy and with reduced toxicity be
developed to treat patients with R/R NHL. Recent research has high￾lighted the importance of epigenetic regulatory mechanisms in the
context of cancer progression. Histone deacetylase (HDAC)
downregulation has been shown to increase the susceptibility of tumor
cells to apoptotic cell death while also suppressing proliferation,
angiogenesis, migration, differentiation, and chemoresistance in a range
of cancers [5]. Combining HDAC inhibitors with traditional chemo￾therapy drugs may therefore be a viable approach to more reliably
treating R/R NHL patients.HDAC inhibitor Vorinostat (SAHA) combined
with azacitidine resulted in 88 % event-free and overall survival rates in
T cell lymphoma patients [6]. Anther HDAC inhibitor romidepsin
(FR901228) combining with CHOP showed good therapeutic effect with
an overall survival of 71 % in newly diagnosed PTCL patients [7]. SAHA
combined with rituximab or R− CHOP showed enhanced effects, espe￾cially in DLBCL patients with an 81 % ORR [8].
CUDC-101 is a novel HDAC inhibitor that has also been shown to
inhibit other key signaling pathways associated with oncogenesis
including the epidermal growth factor receptor (EGFR), Her2, and
MAPK pathways [9]. As such, CUDC-101 exhibits broad anti-tumor ac￾tivity and has been found to help protect against the metastasis and
recurrence of pancreatic cancer when used in combination with
* Corresponding authors at: Research center of Yanbian University Hospital, Jilin, Yanji, 133000, China.
E-mail address: [email protected] (S.-Y. Jin). 1 Contribute equally.
Contents lists available at ScienceDirect
Leukemia Research
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Received 4 January 2021; Received in revised form 24 February 2021; Accepted 28 February 2021
chemotherapeutic drugs such as gemcitabine [10]. Whether CUDC-101
exhibits similar levels of combinatorial synergy in the context of he￾matologic malignancies, however, remains to be established. However,
monotherapy treatment with either gemcitabine or HDAC inhibitors has
been shown to be effective in the treatment of R/R NHL in some in￾stances [11].
Given these prior findings, we designed the present study to assess
the impact of combined CUDC-101 and gemcitabine treatment on
human NHL cells in order to understand the molecular basis for any
synergistic interactions between these two anti-tumor drugs. We found
that CUDC-101 and gemcitabine co-treatment significantly impaired
NHL cell proliferation and induced the apoptotic death of these cancer
cells in vitro. Together, our findings may thus highlight a novel thera￾peutic approach to the treatment of NHL, while also advancing current
understanding of the molecular mechanisms whereby CUDC-101 func￾tions in clinical contexts.
2. Materials and methods
2.1. Cell culture
The human cutaneous T cell lymphoma (CTCL) Hut-78 (Sezary
Syndrome) cell line was obtained from the Shanghai Cell Bank of the
Chinese Academy of Sciences (Shanghai, China). The human diffuse
large B cell lymphoma (DLBCL) Pfeiffer cell line was obtained from the
American Type Culture Collection (ATCC, VA, USA). All cells were
cultured in RPMI-1640 (Gibco, MA, USA) containing 10 % fetal bovine
serum (Invitrogen) and penicillin/streptomycin in a 37 ̊
C 5% CO2
2.2. Reagents and antibodies
Gemcitabine (HANSOH PHARMA, China) was reconstituted in saline
solution, while DMSO was used to reconstitute CUDC-101 (MedChem
Express, China). Antibodies specific for PI3K, AKT, p-AKT, p-EGFR,
cleaved caspase-3, cleaved caspase-9, cleaved caspase-8, HDAC1,
HDAC3, HDAC6, Bax, Bcl-2, ERK1/2, p-ERK1/2, and β-actin were ob￾tained from Cell Signaling Technology (MA, USA).
2.3. CCK-8 assay
Cells were initially plated in 96-well plates (1.5 × 105/well), and
were incubated with appropriate treatments (the concentrations are
respectively 12.5 nM, 25 nM, 50 nM, 100 nM, 200 nM, 400 nM, 800 nM,
1600 nM) for 48 h, after which 10 u L of CCK-8 solution was added per
well. Cells were then incubated for an additional 4 h, after which
absorbance at 450 nm was evaluated via microplate reader (Bio-Rad
Model 680, CA, USA). All samples were evaluated in quintuplicate, and
IC50 concentrations were computed using Graphpad Prism 7. The Cal￾cusyn software (Biosoft, MO, USA) was used to calculate the combina￾tion index (CI) for these treatments. For cell treatment, final doses of 50
nM or 100 nM gemcitabine and 50 nM CUDC-101 were used alone or in
2.4. Cell apoptosis assay
Cells were initially plated in 6-well plates and were treated with
gemcitabine and/or CUDC-101 for 48 h. Cells were then collected,
washed using PBS, and stained for 15 min with Annexin V-FITC/PI prior
to flow cytometric analysis.
2.5. Western blotting
Following a 48 h treatment with gemcitabine and/or CUDC-101 or
vehicle control, cells were lysed in a 100 u L volume of RIPA buffer
containing PMSF and phosphatase inhibitor cocktail (Suolaibao, Beijing
city, China). A BCA assay (Bio-Rad Laboratories, Inc.) was then used to
quantify protein levels in these samples, after which proteins were
separated via SDS-PAGE, transferred to PVDF membranes with the
Semmy Dry instrument (Bio; USA), and subsequently detected using
appropriate primary and secondary antibodies and chemiluminescent
2.6. Statistical analysis
Data were analyzed in triplicate, and are given as means ± SD. Data
were compared via Student’s t-tests or ANOVAs as appropriate using
SPSS v19.0, with P < 0.05 as the significance threshold.
3. Results
3.1. CUDC-101 and gemcitabine synergize to reduce the viability of
lymphoma cells
We began by utilizing a CCK-8 assay to evaluate the impact of CUDC-
101 and/or gemcitabine treatment on the HUT78 and Pfeiffer NHL cell
lines following a 48 h treatment period. The cell proliferation assay
results indicated that an increased concentration of 10–1000 nM gem￾citabine or 10–1000 nM CUDC-101 inhibited the proliferation of HUT78
and Pfeiffer cells (Fig. 1A) in a dose-dependent manner. More impor￾tantly, the isobologram analysis indicated that the effect of the com￾bined treatment was highly synergistic in HUT78 line (combination
index, CI = 0.35) when the concentration of gemcitabine and CUDC-101
were 50 nM and 50 nM, respectively. Similarly, synergistic effects of
gemcitabine plus CUDC-101 were also observed in Pfeiffer line with CI
values below 1(Fig. 1B). We therefore next sought to more fully explore
the synergistic effect of combination CUDC-101 and gemcitabine treat￾ment on NHL cells. We next measured the incidence of apoptotic cell
death among NHL cells treated with CUDC-101 and/or gemcitabine,
revealing that combination treatment with both of these agents induced
a 14.74 % and 15.29 % increase in early apoptosis and a 28.17 % and
38.51 % in late apoptosis in HUT78 and Pfeiffer cells, respectively.
Combination treatment was significantly more effective than gemcita￾bine monotherapy only, induced a 42.91 % and 53.8 % increase in early
and late apoptosis in HUT78 and Pfeiffer cells, respectively (Fig. 1C).
These results suggest that CUDC-101 synergizes with gemcitabine to
suppress the viability of lymphoma cells.
3.2. CUDC-101 and gemcitabine promote the death of NHL cells via the
EGFR/PI3K/Akt and Erk pathways
Apoptotic cell death typically occurs following caspase 8 and caspase
3 activation. As such, we measured cleaved caspase 3 and caspase 8
levels in cells that had been treated with CUDC-101 and/or gemcitabine.
Consistent with our above findings, cleaved caspase 3/8 levels rose
significantly in cells subjected to combination treatment relative to
levels in cells treated with gemcitabine alone. Caspase 3 activation can
occur following the loss of mitochondrial membrane potential, which is
regulated by the Bcl-2 and Bax proteins [12,13]. We found that
CUDC-101 treatment significantly increased the Bax/Bcl-2 ratio in
gemcitabine-treated NHL cells relative to cells treated with gemcitabine
alone (Fig. 2A). These findings suggest that CUDC-101 can thus increase
NHL cell sensitivity to apoptotic death. We further evaluated the un￾derlying signaling pathways associated with these findings. In prior
studies, CUDC-101 and gemcitabine combination treatment has been
shown to drive the death of pancreatic cancer cells via the EGFR/￾MAPK/AKT and Erk signaling pathways, which are key regulators of the
survival and metastasis of cancer cells [14–17]. We therefore analyzed
EGFR signaling cascades in NHL cells following treatment with
CUDC-101 and/or gemcitabine. We found that treatment with one or
both of these agents significantly decreased EGFR, PI3K, AKT, and
p-ERK expression levels in HUT78 and Pfeiffer cells, while MAPK
expression was unaffected (Fig. 2B). This suggests that the mechanisms
whereby CUDC-101 and gemcitabine induce NHL cell apoptosis differ
from the mechanisms whereby they kill pancreatic cancer cells. Overall,
these results demonstrate that CUDC-101 and gemcitabine synergize to
promote NHL cell apoptosis via modulating the EGFR/PI3K/Akt and Erk
3.3. CUDC-101 enhances the chemosensitivity of gemcitabine-treated
NHL cells via modulating HDAC signaling pathways
HDAC inhibitors are frequently used in the context of a range of
cancer types, including both primary and R/R NHL [18,19]. CUDC-101
is a small molecule HDAC inhibitor, and we therefore sought to deter￾mine whether HDAC signaling is related to the ability of CUDC-101 and
gemcitabine to induce the apoptotic death of NHL cells. We found that
CUDC-101 treatment significantly reduced HDAC6 protein levels by 35
% and 40 % in HUT78 and Pfeiffer cells, respectively, with this reduction
being comparable to that observed upon CUDC-101 and gemcitabine
co-treatment of these cells (Fig. 3). This suggests that CUDC-101 may
increase the susceptibility of NHL cells to gemcitabine-induced
apoptosis via inhibiting HDAC expression and activity.
4. Discussion
While the development of chemotherapy has improved the outcomes
associated with many cancers, a large proportion of NHL patients still
suffer from incurable disease [20]. The development of reliable
chemotherapeutic regimens capable of preventing the progression of
aggressive forms of R/R NHL such as DLBCL, mantle-cell lymphoma
(MCL), Burkitt’s lymphoma (BL), follicular lymphoma (FL), and pe￾ripheral T-cell lymphoma (PTCL), remains challenging. DLBLC causes
the majority of B cell NHL cases in adults (75 %) [21]. In this study, we
therefore assessed the ability of CUDC-101 and/or gemcitabine to
induce the death of the human DLBCL and T cell lymphoma cells
(Pfeiffer and HUT-78 cells, respectively).
R/R NHL primarily develops as a consequence of tumor cell che￾moresistance [22]. Gemcitabine is a first-line therapy used to treat some
cases of aggressive R/R NHL alone or in combination with rituximab or
copanlisib (a pan-class I PI3K inhibitor) [9]. However, in some instances
tumor cells develop resistance to these treatments, resulting in tumor
recurrence [23]. Combination treatment of pancreatic cancer using
gemcitabine and an HDAC inhibitor has been shown to prevent metas￾tasis or recurrence [8]. Whether this same combination strategy can
effectively treat R/R NHL, however, remains uncertain. In the present
Fig. 1. CUDC-101 and gemcitabine synergistically mitigated lymphoma cell viability.
A. Cell proliferation in the NHL cell lines following dose dependently treatment with the CUDC-101 for 48 h was measured by CCK8 assay. Combination of CUDC-101
(12.5 nM, 25 nM, 50 nM, 100 nM, 200 nM, 400 nM, 800 nM, 1600 nM) and gemcitabine(12.5 nM, 25 nM, 50 nM, 100 nM, 200 nM, 400 nM, 800 nM, 1600 nM)
synergistically inhibited the viability of PC cells compared with single agents (*P < 0.05, **P < 0.01). B. The combination index (CI) was calculated according to the
approach described by Chou and Talalay. CI = 1 indicates an additive effect, CI < 1 a synergistic effect, and CI > 1 an antagonistic effect. The isobologram analysis
indicated that the effect of the combined treatment (HUT78 gemcitabine 50 nM and CUDC-101 50 nM) was highly synergistic in HUT78(CI = 0.35) cell line,
similarly, synergistic effects of the combined treatment (Pfeiffer gemcitabine 100 nM and CUDC-101 50 nM) was also observed in the Pfeiffer cell line (CI = 0.35). C.
Apoptotic cells were analyzed by flowcytometry in annexin V-FITC/PI stained-NHL cells after treatment with CUDC-101(HUT-78 50 nM, Pfeiffer 50 nM) and
gemcitabine (HUT-78 50 nM, Pfeiffer 100 nM) alone or co-treatment(HUT-78 gemcitabine 50 nM and CUDC-101 50 nM, Pfeiffer gemcitabine 50 nM and CUDC-101
100 nM) for 48 h. (*P < 0.05, **P < 0.01)
study, we determined that the HDAC inhibitor CUDC-101 induced NHL
cellular apoptosis when used as a single agent, and also markedly
enhanced the gemcitabine-induced apoptotic death of these cells. We
found that treatment with CUDC-101 was associated with an increased
Bax/Bcl2 ratio and enhanced caspase 3/8 cleavage in treated cells,
resulting in impaired proliferation and viability. This is consistent with
prior studies which have found that gemcitabine and CUDC-101 can
more effectively induce pancreatic cancer cell apoptosis relative to
gemcitabine alone [8]. CUDC-101 can induce the death of cells that
would otherwise survive single-agent gemcitabine treatment. We also
found that CUDC-101 additionally reduced Bcl-2 protein levels in cells
that had been treated with gemcitabine. As Bcl-2 inhibitors have been
suggested as viable first-line treatments for R/R NHL [24], suggesting
that CUDC-101 may exhibit Bcl-2 inhibitor-like effects in NHL cells.
Many signaling pathways modulate the balance between cell sur￾vival and apoptosis. We assessed the ability of CUDC-101 to induce
apoptotic death via inducing the downregulation of p-EGFR, PI3K/Akt,
and ERK signaling pathway components in gemcitabine-treated NHL
cells. EGFR signaling induced the activating of many downstream
signaling pathways including the PI3K, AKT, RAS/RAF/MEK/MAPK/
ERK, protein kinase C (PKC), Src, and JAK/STAT pathways [25]. We
determined that CUDC-101 can reduce signaling via the EGFR/PI3￾K/AKT and ERK cascades but not the MAPK pathway in
gemcitabine-treated NHL cells. This is distinct from findings in pancre￾atic cancer wherein combination gemcitabine and CUDC-101 treatment
were able to suppress EGFR/MAPK/ERK signaling to suppress differ￾entiation and enhance apoptotic cell death. EGFR/PI3K/Akt and ERK
signaling mechanisms tightly regulate tumor cell survival invasion, and
metastasis [18,19,26], and PI3K/AKT signaling has been shown to
control the pathogenesis of certain forms of lymphoma. Consistent with
this, PI3K/AKT inhibitors have been explored as novel first-line agents
for the treatment of NHL [27,28]. Our results suggesting that CUDC-101
inactivates the EGFR/PI3K/AKT and ERK pathways in
gemcitabine-treated cells are promising, as they highlight potential
modalities whereby CUDC-101 may be used as a PI3K/AKT inhibitor for
the treatment of NHL.
Herein, we found that CUDC-101 treatment decreased HDAC protein
levels in gemcitabine-treated cells. The CUDC-101 IC50 calculated in the
Fig. 2. Combination with CUDC-101 and gemcitabine synergistically provoked lymphoma cell apoptosis compared with single administration via EGFR/PI3K/Akt
and Erk pathway. A.Expression levels of cl-caspase 3, cl-caspase8,Bax and Bcl2 were detected by western blot analysis after CUDC101 and/or gemcitabine incubated
NHL cells. (*P < 0.05, **P < 0.01). B.Western blot analysis showed p-EGFR, PI3K, p-Akt, p-4EBP1 and p-Erk proteins in NHL cells following CUDC-101 and/or
gemcitabine for 48 h (*P < 0.05, **P < 0.01).
present study was 4.4 nM, in line with that of the HDAC inhibitor vor￾inostat (SAHA; 40 nM) [29]. HDAC enzymes regulate chromatin acces￾sibility and gene transcription, and excessive HDAC activity can result in
malignant cell transformation as a consequence of transcriptional
changes. As such, HDAC inhibitors have been identified as potentially
promising anti-cancer agents for the treatment of NHL and other cancers
[30]. In line with data from the Oncomine database (www.oncomine.
org), we determined that CUDC-101 treatment reduced HDAC6 levels
in gemcitabine-treated NHL cells. Was also detected slight decreases in
HDAC1 and HDAC3 in Pfeiffer cells following combination treatment.
HDAC1 is commonly associated with the proliferation and chemo￾resistance of cancer cells, while HDAC3 is associated with the differen￾tiation and proliferation of tumor cells, and HDAC6 plays important
roles in controlling tumor cell angiogenesis and migration [5]. Consis￾tent with these past findings, we determined that CUDC-101 treatment
increased the Bcl2/Bax ratio and inhibited EGFR/PI3K/AKT and ERK
signaling, thereby impacting the viability and proliferation of these NHL
cells. The present study is the first to our knowledge to have explored the
anti-tumor efficacy of gemcitabine and CUDC-101 co-treatment in NHL
cells and to explore the molecular mechanisms underlying this process.
We determined that CUDC-101 treatment increased the chemo￾sensitivity of these cells via modulating the HDAC, Bax/Bcl-2, PI3K/Akt,
and Erk signaling pathways. Given that Bcl-2 and PI3K signaling in￾hibitors are already used to treat certain hematological malignancies,
these findings suggest that CUDC-101 may be a viable combination
therapeutic agent that can improve tumor clearance while potentially
reducing the incidence of treatment-related toxicity and complications.
CUDC-101 as a multi-targeting drug has merits over single-target drugs,
since generally excessive promiscuity could result in adverse-effects
caused by interactions with polypharmacology of individual
anti-target agents [31]. Importantly, we found that CUDC-101 induced
the apoptosis of gemcitabine-treated NHL cells via modulating HDAC6
expression and related HDAC signaling.
5. Conclusion
In summary, the results of the present study demonstrate that CUDC-
101 can induce NHL cell apoptosis alone or in combination with gem￾citabine. In addition, we have offered insights into the molecular
mechanisms whereby CUDC-101 sensitizes these tumor cells to
apoptotic death, underscoring the potential clinical utility of CUDC-101
for the treatment of R/R NHL.
Declaration of Competing Interest
The authors declare no conflict of interest.
No applicable.
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