Therapeutic efficacy of a novel βIII/βIV-tubulin inhibitor (VERU-111) in pancreatic cancer.

Published on Jan 23, 2019in Journal of Experimental & Clinical Cancer Research7.068
· DOI :10.1186/S13046-018-1009-7
Vivek K. Kashyap8
Estimated H-index: 8
(UTHSC: University of Tennessee Health Science Center),
Qinghui Wang9
Estimated H-index: 9
(UTHSC: University of Tennessee Health Science Center)
+ 10 AuthorsSubhash C. Chauhan49
Estimated H-index: 49
(UTHSC: University of Tennessee Health Science Center)
The management of pancreatic cancer (PanCa) is exceptionally difficult due to poor response to available therapeutic modalities. Tubulins play a major role in cell dynamics, thus are important molecular targets for cancer therapy. Among various tubulins, βIII and βIV-tubulin isoforms have been primarily implicated in PanCa progression, metastasis and chemo-resistance. However, specific inhibitors of these isoforms that have potent anti-cancer activity with low toxicity are not readily available. We determined anti-cancer molecular mechanisms and therapeutic efficacy of a novel small molecule inhibitor (VERU-111) using in vitro (MTS, wound healing, Boyden chamber and real-time xCELLigence assays) and in vivo (xenograft studies) models of PanCa. The effects of VERU-111 treatment on the expression of β-tubulin isoforms, apoptosis, cancer markers and microRNAs were determined by Western blot, immunohistochemistry (IHC), confocal microscopy, qRT-PCR and in situ hybridization (ISH) analyses. We have identified a novel small molecule inhibitor (VERU-111), which preferentially represses clinically important, βIII and βIV tubulin isoforms via restoring the expression of miR-200c. As a result, VERU-111 efficiently inhibited tumorigenic and metastatic characteristics of PanCa cells. VERU-111 arrested the cell cycle in the G2/M phase and induced apoptosis in PanCa cell lines via modulation of cell cycle regulatory (Cdc2, Cdc25c, and Cyclin B1) and apoptosis - associated (Bax, Bad, Bcl-2, and Bcl-xl) proteins. VERU-111 treatment also inhibited tumor growth (P < 0.01) in a PanCa xenograft mouse model. This study has identified an inhibitor of βIII/βIV tubulins, which appears to have excellent potential as monotherapy or in combination with conventional therapeutic regimens for PanCa treatment.
📖 Papers frequently viewed together
119 Citations
#1Prashanth K.B. Nagesh (UTHSC: University of Tennessee Health Science Center)H-Index: 10
#2Elham Hatami (UTHSC: University of Tennessee Health Science Center)H-Index: 6
Last. Murali M. Yallapu (UTHSC: University of Tennessee Health Science Center)H-Index: 34
view all 9 authors...
Endoplasmic reticulum (ER) stress is an intriguing target with significant clinical importance in chemotherapy. Interference with ER functions can lead to the accumulation of unfolded proteins, as detected by transmembrane sensors that instigate the unfolded protein response (UPR). Therefore, controlling induced UPR via ER stress with natural compounds could be a novel therapeutic strategy for the management of prostate cancer. Tannic acid (a naturally occurring polyphenol) was used to examine t...
15 CitationsSource
#1Sonam Kumari (UTHSC: University of Tennessee Health Science Center)H-Index: 8
#2Sheema Khan (UTHSC: University of Tennessee Health Science Center)H-Index: 23
Last. Meena Jaggi (UTHSC: University of Tennessee Health Science Center)H-Index: 36
view all 7 authors...
Pancreatic tumors are rewired for high-glucose metabolism and typically present with exceptionally poor prognosis. Recently, we have shown that MUC13, which is highly expressed in pancreatic tumors, promotes tumor progression via modulation of HER2 receptor tyrosine kinase activity. Herein, we investigate a novel, MUC13-mediated molecular mechanism responsible for higher glucose metabolism in pancreatic tumors. Our results demonstrate that MUC13 expression leads to the activation/nuclear translo...
8 CitationsSource
#1Manoj Amrutkar (University of Oslo)H-Index: 12
#2Ivar P. Gladhaug (University of Oslo)H-Index: 32
Pancreatic ductal adenocarcinoma (PDAC), commonly referred to as pancreatic cancer, ranks among the leading causes of cancer-related deaths in the Western world due to disease presentation at an advanced stage, early metastasis and generally a very limited response to chemotherapy or radiotherapy. Gemcitabine remains a cornerstone of PDAC treatment in all stages of the disease despite suboptimal clinical effects primarily caused by molecular mechanisms limiting its cellular uptake and activation...
131 CitationsSource
#1Bilal Bin Hafeez (UT: University of Tennessee)H-Index: 29
#2Aditya Ganju (UT: University of Tennessee)H-Index: 12
Last. Meena Jaggi (UT: University of Tennessee)H-Index: 36
view all 15 authors...
Ormeloxifene (ORM), is a clinically approved selective estrogen receptor modulator, which has also shown excellent anti-cancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ORM on prostate cancer (PrCa) and elucidate a novel molecular mechanism of its anti-cancer activity. ORM treatment inhibited epithelial to mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, and vimentin, MMPs (MMP2 and MMP3), β-cate...
23 CitationsSource
#1Amelia L. Parker (UNSW: University of New South Wales)H-Index: 7
#2Wee Siang Teo (UNSW: University of New South Wales)H-Index: 7
Last. Maria Kavallaris (UNSW: University of New South Wales)H-Index: 63
view all 4 authors...
Tubulin proteins, as components of the microtubule cytoskeleton perform critical cellular functions throughout all phases of the cell cycle. Altered tubulin isotype composition of microtubules is emerging as a feature of aggressive and treatment refractory cancers. Emerging evidence highlighting a role for tubulin isotypes in differentially influencing microtubule behaviour and broader functional networks within cells is illuminating a complex role for tubulin isotypes regulating cancer biology ...
43 CitationsSource
#1Rashmi Bharti (IIT-KGP: Indian Institute of Technology Kharagpur)H-Index: 13
#2Goutam Dey (IIT-KGP: Indian Institute of Technology Kharagpur)H-Index: 34
Last. Mahitosh Mandal (IIT-KGP: Indian Institute of Technology Kharagpur)H-Index: 62
view all 15 authors...
Selective targeting to the tumor niche remains a major challenge in successful cancer therapy. Somatostatin receptor 2 (SSTR2) is overexpressed in breast cancer cells thus making this receptor an attractive target for selective guidance of ligand-conjugated drug liposomes to the tumor site. In this study, a synthetic somatostatin analogue (SST) was used as SSTR2 targeting agent and Diacerein was employed as therapeutic molecule. Diacerein loaded liposomes (DNL) were prepared and they were furthe...
32 CitationsSource
#1George Sharbeen (UNSW: University of New South Wales)H-Index: 10
#2Josh McCarroll (UNSW: University of New South Wales)H-Index: 3
Last. Phoebe A. Phillips (UNSW: University of New South Wales)H-Index: 33
view all 10 authors...
Pancreatic cancer (PC) is a lethal disease which is characterized by chemoresistance. Components of the cell cytoskeleton are therapeutic targets in cancer. βIV-tubulin is one such component that has two isotypes—βIVa and βIVb. βIVa and βIVb isotypes only differ in two amino acids at their C-terminus. Studies have implicated βIVa-tubulin or βIVb-tubulin expression with chemoresistance in prostate, breast, ovarian and lung cancer. However, no studies have examined the role of βIV-tubulin in PC or...
8 CitationsSource
#1Xiaoxin Wu (UTHSC: University of Tennessee Health Science Center)H-Index: 1
#2Qinghui Wang (UTHSC: University of Tennessee Health Science Center)H-Index: 9
Last. Wei LiH-Index: 54
view all 3 authors...
Microtubules are involved in many critical cellular processes including cell division, cell shape maintenance, vesicle transportation and motility regulation. Disruption of tubulin dynamics is a well-validated cancer drug target with several FDA approved, highly efficacious tubulin inhibitors targeting the taxane or the vinca binding sites. Despite the tremendous successes for these clinical tubulin inhibitors, their limitations are also apparent, particularly in the development of transporter m...
34 CitationsSource
#1Iwao Ojima (SBU: Stony Brook University)H-Index: 82
#2Brendan Lichtenthal (SBU: Stony Brook University)H-Index: 2
Last. Xin Wang (SBU: Stony Brook University)H-Index: 3
view all 5 authors...
Introduction:Paclitaxel and docetaxel were two epoch-making anticancer drugs and have been successfully used in chemotherapy for a variety of cancer types. In the year 2010, a new taxane, cabazitaxel, was approved by FDA for use in combination with prednisone for the treatment of metastatic hormone-refractory prostate cancer. Albumin-bound paclitaxel (nab™-paclitaxel; abraxane) nanodroplet formulation was another notable invention (FDA approval 2005 for refractory, metastatic, or relapsed breast...
71 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...
Abstract Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Can...
10.8k CitationsSource
Cited By11
#1Hongmei CuiH-Index: 1
#2Qinghui WangH-Index: 9
Last. Wei LiH-Index: 54
view all 4 authors...
Melanoma is one of the deadliest skin cancers having a five-year survival rate around 15-20%. An overactivated MAPK/AKT pathway is well-established in BRAF mutant melanoma. Vemurafenib (Vem) was the first FDA-approved BRAF inhibitor and gained great clinical success in treating late-stage melanoma. However, most patients develop acquired resistance to Vem within 6-9 months. Therefore, developing a new treatment strategy to overcome Vem-resistance is highly significant. Our previous study reporte...
#1Minghuan Gao (SPU: Shenyang Pharmaceutical University)H-Index: 1
#2Tong Liu (SPU: Shenyang Pharmaceutical University)H-Index: 1
Last. Yingliang Wu (SPU: Shenyang Pharmaceutical University)H-Index: 16
view all 10 authors...
Abstract Lung cancer is the most common cause of cancer-related death worldwide. The occurrence of multidrug resistance (MDR) affects the therapeutic efficacy of chemotherapeutics. Therefore, to develop new anticarcinogen which can overcome MDR is urgent. Here, the novel microtubule inhibitor 5-(4-ethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazol-3-amine (YAN) exhibited strong cytotoxicity towards A549 and MDR-phenotype A549/Taxol cells. We demonstrated that YAN was a poor substrate of P...
1 CitationsSource
#1Sarah T. BoyleH-Index: 7
#2Parul Mittal (UniSA: University of South Australia)H-Index: 7
Last. Manuela Klingler-HoffmannH-Index: 13
view all 6 authors...
Tumorigenesis involves a complex interplay between genetically modified cancer cells and their adjacent normal tissue, the stroma. We used an established breast cancer mouse model to investigate this inter-relationship. Conditional activation of Rho-associated protein kinase (ROCK) in a model of mammary tumorigenesis enhances tumor growth and progression by educating the stroma and enhancing the production and remodeling of the extracellular matrix. We used peptide matrix-assisted laser desorpti...
#1Filip Borys (Nencki Institute of Experimental Biology)H-Index: 1
#2Ewa Joachimiak (Nencki Institute of Experimental Biology)H-Index: 11
Last. Hanna Fabczak (Nencki Institute of Experimental Biology)H-Index: 15
view all 4 authors...
Microtubules (MTs), highly dynamic structures composed of α- and β-tubulin heterodimers, are involved in cell movement and intracellular traffic and are essential for cell division. Within the cell, MTs are not uniform as they can be composed of different tubulin isotypes that are post-translationally modified and interact with different microtubule-associated proteins (MAPs). These diverse intrinsic factors influence the dynamics of MTs. Extrinsic factors such as microtubule-targeting agents (M...
4 CitationsSource
#1Advait B. Shetty (UTHSC: University of Tennessee Health Science Center)H-Index: 3
#2Prashanth K.B. Nagesh (University of Texas at Austin)H-Index: 10
Last. Subhash C. Chauhan (University of Texas at Austin)H-Index: 49
view all 7 authors...
Pancreatic cancer (PanCa) is a highly lethal disease with a poor 5 year survival rate, less than 7%. It has a dismal prognosis, and more than 50% of cases are detected at an advanced and metastatic stage. Gemcitabine (GEM) is a gold standard chemotherapy used for PanCa treatment. However, GEM-acquired resistance in cancer cells is considered as a major setback for its continued clinical implementation. This phenomenon is evidently linked to de novo lipid synthesis. PanCa cells rely on de novo li...
#1Vivek Kumar Kashyap (UTHSC: University of Tennessee Health Science Center)H-Index: 1
#1Vivek K. Kashyap (UTHSC: University of Tennessee Health Science Center)H-Index: 8
Last. Subhash C. Chauhan (UTHSC: University of Tennessee Health Science Center)H-Index: 49
view all 14 authors...
Abstract In this study, we investigated the therapeutic efficacy of VERU-111 in vitro and in vivo model systems of cervical cancer. VERU-111 treatment inhibited cell proliferation and, clonogenic potential, induce accumulation of p53 and down regulated the expression of HPV E6/E7 expression in cervical cancer cells. In addition, VERU-111 treatment also decreased the expression of phosphorylation of Jak2 (TyR1007/1008) and STAT3 at Tyr705 and Ser727. VERU-111 treatment arrested cell cycle in the ...
2 CitationsSource
#1Prashanth K.B. Nagesh (University of Texas at Austin)H-Index: 10
#2Pallabita Chowdhury (UTHSC: University of Tennessee Health Science Center)H-Index: 12
Last. Murali M. Yallapu (University of Texas at Austin)H-Index: 34
view all 9 authors...
Prostate cancer (PCa) cells exploit the aberrant lipid signaling and metabolism as their survival advantage. Also, intracellular storage lipids act as fuel for the PCa proliferation. However, few studies were available that addressed the topic of targeting lipid metabolism in PCa. Here, we assessed the tannic acid (TA) lipid-targeting ability and its capability to induce endoplasmic reticulum (ER) stress by reactive oxygen species (ROS) in PCa cells. TA exhibited dual effects by inhibiting lipog...
5 CitationsSource
#1Eavan C McLoughlin (Trinity College, Dublin)H-Index: 1
#2Niamh M. O’Boyle (Trinity College, Dublin)H-Index: 14
It is over 50 years since the discovery of microtubules, and they have become one of the most important drug targets for anti-cancer therapies. Microtubules are predominantly composed of the protein tubulin, which contains a number of different binding sites for small-molecule drugs. There is continued interest in drug development for compounds targeting the colchicine-binding site of tubulin, termed colchicine-binding site inhibitors (CBSIs). This review highlights CBSIs discovered through dive...
38 CitationsSource
#1Mohammad Amjad Kamal (KAU: King Abdulaziz University)H-Index: 51
#2Maryam H. Al-Zahrani (KAU: King Abdulaziz University)H-Index: 4
Last. Firoz Anwar (KAU: King Abdulaziz University)H-Index: 25
view all 9 authors...
Cancer cells are altered with cell cycle genes or they are mutated that lead to high rate of proliferation compared to normal cells. Alteration in these genes lead to mitosis dysregulation and becomes the very bases tumour progression and resistance to many drugs. The drugs which act on the cell cycle fails to arrest the process, making a cancer cell non responsive to apoptosis or cell death. Vinca alkaloids and taxanes falls in this category and referred as antimitotic agents. Microtubule prote...
1 CitationsSource