Novel Mechanistic Insight into the Anticancer Activity of Cucurbitacin D against Pancreatic Cancer (Cuc D Attenuates Pancreatic Cancer).

Published on Dec 31, 2019in Cells4.366
· DOI :10.3390/CELLS9010103
Mohammed Sikander7
Estimated H-index: 7
(UTHSC: University of Tennessee Health Science Center),
Shabnam Malik8
Estimated H-index: 8
(UTHSC: University of Tennessee Health Science Center)
+ 8 AuthorsSubhash C. Chauhan49
Estimated H-index: 49
Sources
Abstract
Pancreatic cancer (PanCa) is one of the leading causes of death from cancer in the United States. The current standard treatment for pancreatic cancer is gemcitabine, but its success is poor due to the emergence of drug resistance. Natural products have been widely investigated as potential candidates in cancer therapies, and cucurbitacin D (Cuc D) has shown excellent anticancer properties in various models. However, there is no report on the therapeutic effect of Cuc D in PanCa. In the present study, we investigated the effects of the Cuc D on PanCa cells in vitro and in vivo. Cuc D inhibited the viability of PanCa cells in a dose and time dependent manner, as evident by MTS assays. Furthermore, Cuc D treatment suppressed the colony formation, arrest cell cycle, and decreased the invasion and migration of PanCa cells. Notably, our findings suggest that mucin 13 (MUC13) is down-regulated upon Cuc D treatment, as demonstrated by Western blot and qPCR analyses. Furthermore, we report that the treatment with Cuc D restores miR-145 expression in PanCa cells/tissues. Cuc D treatment suppresses the proliferation of gemcitabine resistant PanCa cells and inhibits RRM1/2 expression. Treatment with Cuc D effectively inhibited the growth of xenograft tumors. Taken together, Cuc D could be utilized as a novel therapeutic agents for the treatment/sensitization of PanCa.
📖 Papers frequently viewed together
14 Citations
1 Citations
References45
Newest
#1Mohammed Sikander (UT: University of Tennessee)H-Index: 7
#2Shabnam Malik (UT: University of Tennessee)H-Index: 8
Last. Subhash C. ChauhanH-Index: 49
view all 12 authors...
Prostate cancer (PrCa) metastasis is the major cause of mortality and morbidity among men. Metastatic PrCa cells are typically adopted for aberrant glucose metabolism. Thus, chemophores that reprogram altered glucose metabolic machinery in cancer cells can be useful agent for the repression of PrCa metastasis. Herein, we report that cucurbitacin D (Cuc D) effectively inhibits glucose uptake and lactate production in metastatic PrCa cells via modulating glucose metabolism. This metabolic shift by...
13 CitationsSource
#1Voura M (A.U.Th.: Aristotle University of Thessaloniki)H-Index: 1
#1Maria Voura (A.U.Th.: Aristotle University of Thessaloniki)H-Index: 2
Last. Md. Imtaiyaz Hassan (Jamia Millia Islamia)H-Index: 35
view all 9 authors...
Microtubule affinity regulating kinase 4 (MARK4) becomes a unique anti-cancer drug target as its overexpression is responsible for different types of cancers. In quest of novel, effective MARK4 inhibitors, some acridone derivatives were synthesized, characterized and evaluated for inhibitory activity against human MARK4. Among all the synthesized compounds, three (7b, 7d and 7f) were found to have better binding affinity and enzyme inhibition activity in µM range as shown by fluorescence binding...
25 CitationsSource
#1Yanzhen Zhang (Zhengzhou University)H-Index: 3
#2Chun Feng Wang (Zhengzhou University)H-Index: 1
Last. Lian Feng Zhang (Zhengzhou University)H-Index: 1
view all 3 authors...
: Cucurbitacin D (CuD), isolated from plants from the Cucurbitaceae family, is a potential antitumour agent since it inhibits proliferation, migration and metastasis of cancer cells. Despite CuD antitumour activity in cancer cells, the effects of CuD on gastric cancer cell lines remain unclear. The present study aimed to investigate the effects of CuD on gastric cancer cell growth and death. Human gastric cancer cell lines (AGS, SNU1 and Hs746T) were cultured and treated with different concentra...
7 CitationsSource
#1Rebecca L. Siegel (ACS: American Cancer Society)H-Index: 67
#2Kimberly D. Miller (ACS: American Cancer Society)H-Index: 28
Last. Ahmedin Jemal (ACS: American Cancer Society)H-Index: 139
view all 3 authors...
Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2014, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2015, were collected by the Nation...
10.1k CitationsSource
#1Mohammed Sikander (UT: University of Tennessee)H-Index: 7
#2Bilal Bin Hafeez (UT: University of Tennessee)H-Index: 29
Last. Meena Jaggi (UT: University of Tennessee)H-Index: 36
view all 8 authors...
In this study, we for the first time, investigated the potential anti-cancer effects of a novel analogue of cucurbitacin (Cucurbitacin D) against cervical cancer in vitro and in vivo. Cucurbitacin D inhibited viability and growth of cervical cancer cells (CaSki and SiHa) in a dose-dependent manner. IC50 of Cucurbitacin D was recorded at 400 nM and 250 nM in CaSki and SiHa cells, respectively. Induction of apoptosis was observed in Cucurbitacin D treated cervical cancer cells as measured by enhan...
33 CitationsSource
#1Tsukasa Nakanishi (University of Occupational and Environmental Health Japan)H-Index: 4
#2Yuan Song (Hebei Medical University)H-Index: 8
Last. Yasuhiro Yoshida (University of Occupational and Environmental Health Japan)H-Index: 24
view all 8 authors...
We previously reported that the inflammasome inhibitor cucurbitacin D (CuD) induces apoptosis in human leukemia cell lines. In the present study, we investigated the effects of co-treatment with an additional Bcl-xL inhibitor, Z36. Treatment with Z36 induced cell death in leukemia cell lines, with MT-4 cells exhibiting the lowest sensitivity to Z36. Co-treatment of cells with Z36 and CuD resulted in a greater degree of cell death for Hut78 and Jurkat cells than treatment with CuD alone. In contr...
15 CitationsSource
#1Mohd Saif Zaman (UTHSC: University of Tennessee Health Science Center)H-Index: 3
#2Neeraj Chauhan (UTHSC: University of Tennessee Health Science Center)H-Index: 24
Last. Subhash C. ChauhanH-Index: 49
view all 11 authors...
Cervical cancer is one of the most common cancers among women worldwide. Current standards of care for cervical cancer includes surgery, radiation, and chemotherapy. Conventional chemotherapy fails to elicit therapeutic responses and causes severe systemic toxicity. Thus, developing a natural product based, safe treatment modality would be a highly viable option. Curcumin (CUR) is a well-known natural compound, which exhibits excellent anti-cancer potential by regulating many proliferative, onco...
97 CitationsSource
#1Jin Mo Ku (Kyung Hee University)H-Index: 11
#2Soon Re Kim (Kyung Hee University)H-Index: 8
Last. Seong-Gyu Ko (Kyung Hee University)H-Index: 30
view all 7 authors...
Breast cancer is the most common cancer for women and is a major cause of mortality in women. Doxorubicin is a generally used chemotherapy drug for breast cancer. However, multidrug resistance of breast cancer interferes with the chemotherapy. We examined whether cucurbitacin D affects doxorubicin resistance of MCF7/ADR breast cancer cells. Cell viability was measured by MTT assay. Levels of p-STAT3, p-NF-κB, IκB, and caspases were measured by Western blot analysis. Nuclear staining of Stat3 and...
41 CitationsSource
#1Jessica Ann Hall (KU: University of Kansas)H-Index: 8
#2Sahithi Seedarala (KU: University of Kansas)H-Index: 2
Last. Brian S. J. Blagg (KU: University of Kansas)H-Index: 55
view all 6 authors...
Heat shock protein 90 (Hsp90) facilitates the maturation of many newly synthesized and unfolded proteins (clients) via the Hsp90 chaperone cycle, in which Hsp90 forms a heteroprotein complex and relies upon cochaperones, immunophilins, etc., for assistance in client folding. Hsp90 inhibition has emerged as a strategy for anticancer therapies due to the involvement of clients in many oncogenic pathways. Inhibition of chaperone function results in client ubiquitinylation and degradation via the pr...
17 CitationsSource
#1Sargis Dallakyan (Scripps Research Institute)H-Index: 2
#2Arthur J. Olson (Scripps Research Institute)H-Index: 68
Abstract Virtual molecular screening is used to dock small-molecule libraries to a macromolecule in order to find lead compounds with desired biological function. This in silico method is well known for its application in computer-aided drug design. This chapter describes how to perform small-molecule virtual screening by docking with PyRx, which is open-source software with an intuitive user interface that runs on all major operating systems (Linux, Windows, and Mac OS). Specific steps for usin...
607 CitationsSource
Cited By7
Newest
#1Xiukun LinH-Index: 27
#2Ammad Ahmad Farooqi (Brazilian Institute of Geography and Statistics)H-Index: 25
Research over decades has enabled us in developing a better understanding of the multifaceted and heterogeneous nature of cancer. High-throughput technologies have helped the researchers in unraveling of the underlying mechanisms which centrally regulate cancer onset, metastasis and drug resistance. Our rapidly expanding knowledge about signal transduction cascade has added another layer of complexity to already complicated nature of cancer. Deregulation of cell signaling pathways played a linch...
4 CitationsSource
The isolation of chemical compounds from natural origins for medical application has played an important role in modern medicine with a range of novel treatments having emerged from various natural forms over the past decades. Natural compounds have been exploited for their antioxidant, antimicrobial and antitumor capabilities. Specifically, 60% of today’s anticancer drugs originate from natural sources. Moreover, the combination of synthetic and natural treatments has shown applications for (i)...
Source
#1Sunitha Kodidela (UTHSC: University of Tennessee Health Science Center)H-Index: 11
#2Namita Sinha (UTHSC: University of Tennessee Health Science Center)H-Index: 12
Last. Santosh Kumar (UTHSC: University of Tennessee Health Science Center)H-Index: 96
view all 4 authors...
Chemodietary agents are emerging as promising adjuvant therapies in treating various disease conditions. However, there are no adjuvant therapies available to minimize the neurotoxicity of currently existing antiretroviral drugs (ARVs). In this study, we investigated the anti-HIV effect of a chemodietary agent, Cucurbitacin-D (Cur-D), in HIV-infected macrophages using an in-vitro blood–brain barrier (BBB) model. Since tobacco smoking is prevalent in the HIV population, and it exacerbates HIV rep...
Source
#1Xuan WangH-Index: 1
#2Jun Cai (Yangtze University)H-Index: 5
Last. Min Jin (HUST: Huazhong University of Science and Technology)H-Index: 6
view all 8 authors...
Experimental and clinical studies over the past two decades have provided overwhelming evidence that human cancers, including prostate cancer (PCa), harbor cancer stem cells (CSCs) that sustain tumor growth, drive tumor progression and mediate therapy resistance and tumor relapse. Recent studies have also implicated NUMB as a PCa suppressor and an inhibitor of PCa stem cells (PCSCs); however, exactly how NUMB functions in these contexts remains unclear. Here, by employing bioinformatics analysis...
Source
#1Shuai Huang (Guangzhou Medical University)
#2Bihui Cao (Guangzhou Medical University)H-Index: 2
Last. Baoxia Liang (Guangzhou Medical University)H-Index: 1
view all 11 authors...
Cucurbitacin B (CuB) is a widely available triterpenoid molecule that exhibits various biological activities. Previous studies on the anti-tumour mechanism of CuB have mostly focused on cell apoptosis, and research on the ferroptosis-inducing effect has rarely been reported. Herein, we first discovered the excellent cytotoxicity of CuB towards human nasopharyngeal carcinoma cells and elucidated its potential ferroptosis-inducing mechanisms. Morphology alterations of mitochondrial ultrastructure,...
1 CitationsSource
The study describes the synthesis, physicochemical properties, and biological evaluation of polymer therapeutics based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers intended for a tumor-targeted immuno-oncotherapy. Water-soluble linear and cholesterol-containing HPMA precursors were synthesized using controlled reversible addition–fragmentation chain transfer polymerization to reach molecular weight Mn about 2 × 104 g·mol−1 and low dispersity. These linear or self-assembled micellar con...
Source
#1Saleha Anwar (Jamia Millia Islamia)H-Index: 8
#2Anas Shamsi (Jamia Millia Islamia)H-Index: 14
Last. Imtaiyaz Hassan (Jamia Millia Islamia)H-Index: 19
view all 11 authors...
Microtubule affinity regulating kinase (MARK4) is a potential drug target for different types of cancer as it controls the early step of cell division. In this study, we have screened a series of natural compounds and finally identified rosmarinic acid (RA) as a potential inhibitor of MARK4. Molecular docking and 500 ns all-atom simulation studies suggested that RA binds to the active site pocket of MARK4, forming enough number of non-covalent interactions with critical residues and MARK4-RA com...
19 CitationsSource