Radiosensitization of human pancreatic cancer by piperlongumine analogues

Article abstract of DOI:10.1016/j.cclet.2020.08.049

Radiotherapy is commonly used to treat advanced pancreatic cancers and can improve survival by 2 months in combination with gemcitabine. However, prognosis and survival improvement remain unsatisfactory, and effective therapies are urgently needed. Piperlongumine has been demonstrated to have therapeutic potentials against various cancers. In this study, we synthesized a series of piperlongumine derivatives and provided evidence that piperlongumine derivatives could be used as effective radiosensitizers in pancreatic cancer. Two compounds enhanced the radiosensitivity of Panc-1 and SW1990 cells. In a pancreatic bi-flank xenograft tumor model, they significantly inhibited tumor growth. Piperlongumine derivatives could induce reactive oxygen species (ROS) expression and regulate the Keap1-Nrf2 protective pathway with enhancement of radiation-induced DNA damage, G2/M-phase cell cycle arrest, and apoptosis. Collectively, our data offer a proof of concept for the use of piperlongumine derivatives as a novel class of radiosensitizers for the treatment of pancreatic cancer.

Full text of DOI:10.1016/j.cclet.2020.08.049

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CCLET 5826 No. of Pages 5
Chinese Chemical Letters xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Radiosensitization of human pancreatic cancer by
piperlongumine analogues
Hao Maa,e, Yuelin Wud, Wannian Zhanga,c, Huojun Zhangb, Zhenyuan Miaoa,
,
*
Chunlin Zhuanga,c,
*
a
School of Pharmacy, Second Military Medical University, Shanghai 200433, China
Department of Radiation Oncology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China
School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China
b
c
d
e
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Radiotherapy is commonly used to treat advanced pancreatic cancers and can improve survival by
2 months in combination with gemcitabine. However, prognosis and survival improvement remain
unsatisfactory, and effective therapies are urgently needed. Piperlongumine has been demonstrated to
Received 28 May 2020
Received in revised form 31 July 2020
Accepted 30 August 2020
Available online xxx
have therapeutic potentials against various cancers. In this study, we synthesized
a series of
piperlongumine derivatives and provided evidence that piperlongumine derivatives could be used as
effective radiosensitizers in pancreatic cancer. Two compounds enhanced the radiosensitivity of Panc-1
and SW1990 cells. In a pancreatic bi-flank xenograft tumor model, they significantly inhibited tumor
growth. Piperlongumine derivatives could induce reactive oxygen species (ROS) expression and regulate
the Keap1-Nrf2 protective pathway with enhancement of radiation-induced DNA damage, G2/M-phase
cell cycle arrest, and apoptosis. Collectively, our data offer a proof of concept for the use of
piperlongumine derivatives as a novel class of radiosensitizers for the treatment of pancreatic cancer.
© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Piperlongumine
Pancreatic cancer
Radiosensitization
Sensitivity enhancement ratio (SER)
Reactive oxygen species (ROS)
Keap1-Nrf2
Bi-flank xenograft tumor model
Pancreatic cancer is one of the most aggressive cancers, and
chemotherapy remains a main therapeutic strategy for pancreatic
cancer treatment in the clinic [1]. Currently, gemcitabine (10,
Fig. 1) is used as the standard first-line treatment for patients with
pancreatic cancer, exhibiting an improved but unsatisfactory
survival rate in recent decades [2]. Many drug combinations with
gemcitabine have been evaluated. Among these combinations,
gemcitabine plus nab-paclitaxel (Nab-P) exhibited increased
survival of pancreatic cancer patients compared with gemcitabine
alone [3,4]. FOLFIRINOX (fluorouracil, oxaliplatin and irinotecan)
was approved for the treatment of metastatic pancreatic cancer.
The overall survival improved to 11.1 months in the FOLFIRINOX-
treated group from 6.8 months in the gemcitabine-treated group
[5,6]. However, this treatment has been used with caution in the
clinic due to the high toxicity [7–9]. Only a 2-month improvement
in survival (11.1 months vs. 9.2 months) and poor prognosis were
observed in those treated with gemcitabine and radiation weekly
compared with those who concurrently received a standard dose
and schedule of gemcitabine alone [10]. These small improve-
ments hold great promise for the development of effective
therapeutic strategies to treat pancreatic cancer, and novel
therapeutic agents are also urgently needed.
Piperlongumine (1, Fig. 1), a naturally occurring compound
isolated from the root of the plant Piper longum L. [11], exhibits a
broad spectrum of biological activities [12]. It has been proposed
that reactive oxygen species (ROS) enhancement is the main
mechanism of action of compound 1 for killing cancer cells [13]. In
our previous report, a preliminary structure-activity relationship
(SAR) study showed that the two olefins were critical for the
cytotoxicity [14], and introduction of a chloride on the lactam had
favorable effects on the activity [15]. In this study, structure
optimization was focused on the lactam, conducting ring expan-
sion with one additional carbon, and the substituents on the
benzene ring. Representative compounds were selected for
pancreatic cancer cell growth inhibition. These compounds were
used as effective radiosensitizers of pancreatic cancer cells in vitro
* Corresponding authors at: School of Pharmacy, Second Military Medical
University, Shanghai 200433, China.
E-mail addresses: miaozhenyuan@hotmail.com (Z. Miao), zclnathan@163.com
(C. Zhuang).
https://doi.org/10.1016/j.cclet.2020.08.049
1001-8417/© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: H. Ma, et al., Radiosensitization of human pancreatic cancer by piperlongumine analogues, Chin. Chem. Lett.
(2020), https://doi.org/10.1016/j.cclet.2020.08.049

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9d had a GI50 of 1.03 ꢀ 0.02
than that of compound 1 and much higher than that of compound
10 (GI50 = 4.81 ꢀ 2.20 mol/L).
mmol/L, which was 18ꢁ22-fold higher
m
In order to determine the selectivity of piperlongumine
derivatives toward normal cells, we evaluated the cytotoxicity of
9c and 9d against three human normal cell lines, which were
hTERT-HPNE (pancreatic epithelium cells), HKC (renal tubular
epithelium cells) and HIEC (Intestinal epithelium cells). Panc-1 and
SW1990 cells, which are sensitive to piperlongumine treatment,
were selected (Table S2 in Supporting information,). Both
compounds showed significant selectivity index to cancer cell
Fig. 1. The structures of piperlongumine (1) and gemcitabine (10).
and in vivo, and the underlying mechanisms were elucidated. The
synthetic routes of the target compounds were performed in
Scheme S1 (Supporting information).
Based on our previous SAR results, modification of the double
bond of the lactam using chlorine was beneficial to the activity of
the compound, probably due to enhancement of the reactivity of
the Michael acceptor [15]. As shown in Table S1 (Supporting
information), we tested the concentration that causes 50% growth
inhibition (GI50) of piperlongumine derivatives against Panc-1
cells, and gemcitabine was selected as control. Based on the results,
an SAR of piperlongumine derivatives has been summarized as
Scheme S2 (Supporting information). Then, the pancreatic cancer
cell growth inhibition profile was elucidated. Five derivatives (7c,
7d, 9c, 9d and 9l) were selected by the high cytotoxicity toward
Panc-1 cells and their chemical structures. Compound 7c with
trimethoxyl group and 7d without substitution were selected
from 7a-7g. Compound 9c were selected due to its better
lines. The GI50 values of 9c were 0.16 ꢀ 0.02
mol/L against Panc-1 and SW1990, while much lower cytotoxici-
ty was observed in normal cells [hTERT-HPNE cells (1.47 ꢀ 0.24
mol/L, 9-fold, 21-fold), HKC cells (1.11 ꢀ0.05 mol/L, 7-fold, 16-
fold) and HIEC cells (7.90 ꢀ 0.24 mol/L, 49-fold, 113-fold)]. The
GI50 values of 9d were 0.37 ꢀ 0.03 mol/L and 0.24 ꢀ 0.03 mol/L
against Panc-1 and SW1990, and 2.26 ꢀ 0.21 mol/L against
hTERT-HPNE cells (6-fold, 9-fold), 4.16 ꢀ 0.06 mol/L against HKC
mol/L against HIEC cells
(32-fold, 50-fold). However, the parent piperlongumine (1)
showed much lower selectivity index (1ꢁ9-fold) toward three
normal cells. Collectively, the new derivatives selectively inhibit
pancreatic cancer cell growth.
We then determined the potential radiosensitizing effect of
piperlongumine derivatives in pancreatic cancer cells (Panc-1 and
SW1990 cells) using a long-term clonogenic assay. The GI20 were
used to obtain suitable therapeutic windows for radiosensitivity
evaluation [16,17]. The GI20 values of the compounds 1, 7c, 7d, 9c,
9d and 10 against Panc-1 were 409, 27, 206, 100, 130, and 47 nmol/
L, respectively, and against SW1990, the values were 650, 40, 40,
20, 20, and 20 nmol/L, respectively (Fig. S1 in Supporting
information). Then, this dosing regimen was used to test the
radiosensitization effects of these compounds. Cells were pre-
treated with the compounds for 24 h, followed by irradiation at
different doses up to 8 Gy. Compounds were then washed out after
48 h of irradiation. Then, the cells were cultured in compound-free
medium for an additional 7–9 days, allowing colony formation
(Fig. S2 in Supporting information). Under these conditions,
compounds 9c and 9d effectively sensitized both pancreatic
cancer cell lines to radiation with sensitivity enhancement ratios
(SERs) of 1.69, 1.45 (Panc-1) and 1.13, 1.30 (SW1990), respectively.
Compound 7d exhibited an SER of 1.22 toward Panc-1 cells and
only 0.98 toward SW1990 cells. Compounds 1 and 7c exhibited no
apparent sensitization with SERs of ꢁ1.0 toward the two cell lines.
The combination of compound 10 (GI20: 20 nmol/L) and radiation
m
mol/L and 0.07 ꢀ 0.01
m
m
m
m
m
m
m
m
cells (11-fold, 17-fold) and 12.01 ꢀ0.18
m
potency (GI50 = 0.16 ꢀ 0.02
mmol/L) than that of compound 9b
(GI50 = 0.52 ꢀ 0.17 mol/L), which had a same substitution on a
m
different position. Similarly, 9d and 9l were selected for the
acrylamide group and methylphenyl group. As shown in Table 1,
four other pancreatic cell lines (SW1990, Capan-1, Bxpc-3 and
Miapaca-2) were used in this assay. These compounds exhibited
excellent growth inhibitory profiles, similar to that of 10. Panc-1
and SW1990 were the most sensitive cell lines among the five
pancreatic cancer cell lines. The selected compounds exhibited
higher potency than compounds 1 and 10 against these two cell
lines. Compound 9c had the best potency toward SW1990 cells,
with a GI50 value of 70 nmol/L, which was more than 30-fold higher
than that of compound 1 and 2-fold higher than that of compound
10. The selected compounds exhibited relatively low sensitivity in
the other three cell lines. Compound 1 exhibited GI50 values of only
18.5–41.7
improved potency by 4ꢁ20-fold. In particular, compound 9c had
mol/L against Capan-1 cells, which was 15-
mmol/L. The five compounds exhibited significantly
a GI50 of 1.32 ꢀ 0.05
m
fold higher than that of compound 1 and 2-fold higher than that of
compound 10. Against Miapaca-2 cells, compound 9c exhibited a
GI50 in the nanomolar range (0.81 ꢀ0.05
mmol/L), and compound
Table 1
The pancreatic cancer cell growth inhibitory profiles of the five selected piperlongumine derivatives.
a
Compd.
n
R
X
GI50
(mmol/L)
Panc-1
SW1990
Capan-1
Bxpc-3
Miapaca-2
1
1
2
2
2
2
2
–
3,4,5-OMe
3,4,5-OMe
H
p-NHCOCH2Cl
p-NHCOCHCH2
p-4'-Methylbenzenesulfonamide
–
H
3.56 ꢀ 0.21
0.35 ꢀ 0.11
0.63 ꢀ 0.08
0.16 ꢀ 0.02
0.37 ꢀ 0.03
0.21 ꢀ 0.03
1.76 ꢀ 0.20
2.42 ꢀ 1.21
0.21 ꢀ 0.03
0.74 ꢀ 0.06
0.07 ꢀ 0.01
0.24 ꢀ 0.03
0.26 ꢀ 0.07
0.14 ꢀ 0.03
20.30 ꢀ 0.61
5.58 ꢀ 0.25
4.86 ꢀ 0.28
1.32 ꢀ 0.05
2.69 ꢀ 0.10
5.54 ꢀ 1.80
2.55 ꢀ 0.40
41.7 ꢀ 5.89
7.03 ꢀ 0.15
7.48 ꢀ 0.20
5.62 ꢀ 0.74
5.62 ꢀ 0.73
6.02 ꢀ 0.56
6.21 ꢀ 1.15
18.50 ꢀ 2.16
2.81 ꢀ 0.66
5.06 ꢀ 0.44
0.81 ꢀ 0.05
1.03 ꢀ 0.02
1.27 ꢀ 0.13
4.81 ꢀ 2.20
7c
7d
9c
9d
9l
Cl
Cl
Cl
Cl
Cl
–
10
a
Values were determined by CellTiterTM Blue assay. (GI50 value: Mean ꢀ SEM, n = 3).
Please cite this article in press as: H. Ma, et al., Radiosensitization of human pancreatic cancer by piperlongumine analogues, Chin. Chem. Lett.
(2020), https://doi.org/10.1016/j.cclet.2020.08.049

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therapy resulted in a distinct SER of 1.49 in Panc-1 cells, while in
SW1990 cells, the SER value (1.09) was not high. Thus, we
concluded that compounds 9c and 9d are potent radiosensitizers in
pancreatic cancer cells.
cellular ROS and maintenance of the stability of the intracellular
environment [18]. As shown in Fig. 3A, Nrf2 levels in compounds
9c and 9d treated Panc-1 and SW1990 cells were significantly
upregulated in a dose-response manner (10 nmol/L and 100 nmol/
The Panc-1 and SW1990 xenograft models were initially tried,
with only Panc-1 model growing well. Considering our scope of the
piperlongumine-derivative-mediated radiosensitization, we eval-
uated the compound only in the Panc-1 xenograft model.
Compounds 1 (5 mg/kg, i.p./day, 14 days) and 10 (25 mg/kg, i.p.,
twice a week for 2 weeks) were selected as controls. Panc-1 cells
were inoculated subcutaneously into both flanks of nude mice to
compare the activities using the same mouse [17]. Radiation was
delivered directly to the tumor, with the rest of the animal shielded
by using an in-house lead brick. As shown in Fig. 2 and Fig. S3
(Supporting information), administration of compound 1, 9c or 9d
alone, at a dose of 5.0 mg/kg, i.p./day for 14 days, led to tumor
growth inhibitions (TGIs) of 31%, 50% and 34%, respectively, which
were significantly lower than that observed with compound 10
(62%). In addition, no obvious tumor inhibitory activity (only 14%)
was observed using radiation as a single treatment at a dose of 6 Gy
per day for two weeks. In response to treatment with the
combination of piperlongumine derivatives and radiation, tumor
growth was significantly inhibited compared with the effect of
either treatment alone at day 14. The inhibition rate of compound 1
increased from 31% to 44%. The inhibition rate of compound 10
increased from 62% to 73%. The inhibition rates of compounds 9c
and 9d increased from 50% to 73% and 34%–59%, respectively.
Importantly, the combination treatment was well tolerated by the
animals, with a loss of body weight lower than that observed with
Food and Drug Administration (FDA) approved drug 10. The tumors
were then collected to confirm the inhibitory effects. Our results
showed that compounds 9c and 9d effectively sensitized Panc-1
tumor growth to radiotherapy.
L) at 12 h. Accordingly, Keap1, a suppressor of Nrf2, was
significantly downregulated with high doses of compounds 9c
and 9d at 12 h. The regulations were much better than the parent
piperlongumine (1) in the same concentrations. For NQO-1 and
HO-1, two downstream antioxidant enzymes, no significant
changes have been demonstrated for compound 1 treated cells.
Compounds 9c and 9d could markedly increase the expressions of
NQO-1 in a dose-dependent manner in Panc-1 and SW1990 cells at
12 h. These two compounds could also increase the expressions
of HO-1 in Panc-1 and SW1990 cells at 12 h. In addition, 9c and
9d could induce up-regulation of
g-H2AX expression and no
changes in total H2AX in two cell lines, indicating DNA damage
occurred.
To verify whether the Nrf2 protein was involved in the
transcription of downstream proteins and translocated into the
cell nucleus from the cytoplasm, we examined the levels of the
Nrf2 protein in the nucleus and cytoplasm using piperlongumine
derivatives (100 nmol/L) at different time points. As demonstrated
in Fig. 3C, the expression of Nrf2 was significantly translocated into
the nucleus, peaked at 6 h, and then, the trend was reversed, as
detected at 12 h and 24 h. Nrf2 expression decreased steadily
throughout the process in the cytoplasm. We finally tested the
effect of combination therapy on protein expression. As shown in
Fig. 3B, Nrf2 and its downstream protein HO-1 and NQO-1 were
obviously increased by compounds 9c and 9d with radiation (6 Gy)
in a time-dependent manner. Consistent with the SER value,
compound 1 did not affect Nrf2 and HO-1 expression after
irradiation (6 Gy). Given that radiation is closely associated with
DNA damage [19], the expression of g-H2AX was also significantly
We next explored the mechanisms of action of piperlongumine
derivatives at the cellular level. ROS accumulation in pancreatic
cancer cells treated with piperlongumine derivatives was evaluat-
ed using the redox-sensitive fluorescent probe 20,70-dichlorofluor-
escein diacetate (DCFH-DA, Fig. S4 in Supporting information).
Consistent with the observed in vitro and in vivo efficacy,
compounds 9c and 9d exhibited the best ROS induction compared
with the other derivatives in both Panc-1 and SW1990 cells. The
Keap1-Nrf2 pathway is of great importance for the clearance of
enhanced by compounds 1, 9c and 9d. These results were also
confirmed by the immunofluorescence assay (Fig. 3D, Fig. S5 in
Supporting information). The intracellular protein fluorescence
intensity was significantly increased by the combination of the
compounds and radiation. In particular, compounds 9c and 9d
exhibited a greater than 2-fold increase in fluorescence intensity in
combination with radiotherapy and better effects than compound
1. The above results indicate that g-H2AX plays a predominant role
in combination radiotherapy.
Fig. 2. Piperlongumine-derivative-mediated radiosensitization in Panc-1 xenograft tumor model. (A–B) Tumor volume in each group of nude mice. (C) Body weight in each
group of nude mice. (D) Tumor inhibition rate statistics. * P < 0.05, ** P < 0.01. Control is the group treated with normal saline (i.p./d, 14 d).
Please cite this article in press as: H. Ma, et al., Radiosensitization of human pancreatic cancer by piperlongumine analogues, Chin. Chem. Lett.
(2020), https://doi.org/10.1016/j.cclet.2020.08.049

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Fig. 3. Piperlongumine derivatives affect protein expression in pancreatic cancer cells. (A) Effects of different concentrations of piperlongumine derivatives on the expression
of proteins in Panc-1 and SW1990 cells. (B) Effect of piperlongumine derivatives combined with radiotherapy on intracellular protein expression in Panc-1 and SW1990 cells.
(C) Expression of the Nrf2 protein in Panc-1 nucleus and cytoplasm. (D) Immunofluorescence analysis of the effects of piperlongumine derivatives combined with
radiotherapy on
g
-H2AX protein expression in Panc-1 and SW1990 cells (magnification: ꢂ 400). (E) Chemical structures of probes 19a and 19b. (F) Streptavidin pull down of
19a and 19b.Control is the group treated with DMSO group (0.1%).
The piperlongumine is considered to be a pan-assay-interfer-
ence-compounds (PAINS) compound due to the Michael receptor
[20,21]. In order to address the concern, we first screened our
analogues (9c and 9d) through the PAINS compound databases and
they both passed the filter (Fig. S6 in Supporting information).
Second, PAINS compounds typically had a confusing SAR [20,21].
However, the newly obtained piperlongumine derivatives have a
clear SAR (Scheme S2 in Supporting information). Third, based on
the mechanism study, the Keap1-Nrf2 pathway is potentially
involved. In order to further elucidate the potential interaction of
the compounds with Keap1, a pull-down assay [14,22,23] were
performed. We synthesized two biotinylated piperlongumines
(19a and 19b, Fig. 3E, Scheme S3 in Supporting information) by
using click reaction [24] and they showed moderate cytotoxic
effect on Panc-1 cells (Fig. S7 in Supporting information). As shown
in Fig. 3F, Keap1 was dose-dependently pulled down by the probes
in Panc-1 cell lysates, which could be completely competed by the
parent 9c and 9d. Thus, our data indicate that the piperlongumines
bind to Keap1 in Panc-1 cells instead of a promiscuous one.
To further determine the nature of piperlongumine-mediated
radiosensitization, we carried out cell cycle profiling of two cell
lines treated with compounds 1, 9c and 9d; radiation; or
compounds in combination with radiation (Fig. S8 in Supporting
information). The apoptotic rate improved obviously as radiation
added, and the effects were improved by the combination of 1, 9c
or 9d in both cell lines. The G2/M phase block is a marker of DNA
damage [25]. Consistent with the expression of the
g-H2AX
protein, the G2/M phase ratio of the cells increased significantly
after radiation, suggesting increased DNA damage. Compounds 9c
and 9d enhanced the radiation-induced G2/M arrest in Panc-1 and
SW1990 (P < 0.05). Taken together, these results show that the
piperlongumine derivatives combined with radiotherapy could
enhance cellular DNA damage and have a certain sensitizing effect,
leading to apoptosis.
In summary, our study revealed the radiosensitizing activity of
piperlongumine derivatives in pancreatic cancer and elucidated the
mechanisms of action of these compounds in the induction of ROS
expression and regulation of the Keap1-Nrf2 protective pathway by
targeting Keap1 protein in parallel with enhancement of radiation-
induced DNA damage, G2/M-phase cell cycle arrest, and apoptotic
death. In a pancreatic bi-flank xenograft tumor model, 9c and 9d
significantly inhibited tumor growth with high TGI under radiation.
Therefore, our proof-of-concept study provides the first preclinical
evidence for the future development of piperlongumine derivatives
Please cite this article in press as: H. Ma, et al., Radiosensitization of human pancreatic cancer by piperlongumine analogues, Chin. Chem. Lett.
(2020), https://doi.org/10.1016/j.cclet.2020.08.049

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as novel radiosensitizing agents against pancreatic cancer and,
possibly, other types of human cancers.
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The authors declare no conflicts of interest.
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online version, at doi:https://doi.org/10.1016/j.cclet.2020.08.049.
Please cite this article in press as: H. Ma, et al., Radiosensitization of human pancreatic cancer by piperlongumine analogues, Chin. Chem. Lett.
(2020), https://doi.org/10.1016/j.cclet.2020.08.049