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Gastrointestinal (GI) cancers are one of the leading causes of death worldwide. Although various approaches are implemented to improve the health condition of GI patients, none of the treatment protocols promise for eradicating cancer. However, a treatment mechanism against any kind of disease condition is already existing executing inside the human body. The 'immune system' is highly efficient to detect and destroy the unfavourable events of the body including tumor cells. The immune system can restrict the growth and proliferation of cancer. Cancer cells behave much smarter and adopt new mechanisms for hiding from the immune cells. Thus, cancer immunotherapy might play a decisive role to train the immune system against cancer. In this review, we have discussed the immunotherapy permitted for the treatment of GI cancers. We have discussed various methods and mechanisms, periodic development of cancer immunotherapies, approved biologicals, completed and ongoing clinical trials, role of various biopharmaceuticals, and epigenetic factors involved in GI cancer immunotherapies (graphical abstract Figure 1).

Cellular senescence is one of the prevailing issues in cancer therapeutics that promotes cancer relapse, chemoresistance, and recurrence. Patients undergoing persistent chemotherapy often develop drug-induced senescence. Docetaxel, an FDA-approved treatment for prostate cancer, is known to induce cellular senescence which often limits the overall survival of patients. Strategic therapies that counter the cellular and drug-induced senescence are an unmet clinical need. Towards this an effort was made to develop a novel therapeutic strategy that targets and removes senescent cells from the tumors, we developed a nanoformulation of tannic acid−docetaxel self-assemblies (DSAs). The construction of DSAs was confirmed through particle size measurements, spectroscopy, thermal, and biocompatibility studies. This formulation exhibited enhanced in vitro therapeutic activity in various biological functional assays with respect to native docetaxel treatments. Microarray and immunoblot analysis results demonstrated that DSAs exposure selectively deregulated senescence associated TGFβR1/FOXO1/p21 signaling. Decrease in β-galactosidase staining further suggested reversion of drug-induced senescence after DSAs exposure. Additionally, DSAs induced profound cell death by activation of apoptotic signaling through bypassing senescence. Furthermore, in vivo and ex vivo imaging analysis demonstrated the tumor targeting behavior of DSAs in mice bearing PC-3 xenograft tumors. The antisenescence and anticancer activity of DSAs was further shown in vivo by inhibiting TGFβR1 proteins and regressing tumor growth through apoptotic induction in the PC-3 xenograft mouse model. Overall, DSAs exhibited such advanced features due to a natural compound in the formulation as a matrix/binder for docetaxel. Overall, DSAs showed superior tumor targeting and improved cellular internalization, promoting docetaxel efficacy. These findings may have great implications in prostate cancer therapy.

Curcumin is an important bioactive component of turmeric and also one of the important natural products, which has been investigated extensively. The precise mode of action of curcumin and its impact on system level protein networks are still not well studied. To identify the curcumin governed regulatory action on protein interaction network (PIN), an interectome was created based on 788 key proteins, extracted from PubMed literatures, and constructed by using STRING and Cytoscape programs. The PIN rewired by curcumin was a scale-free, extremely linked biological system. MCODE plug-in was used for sub-modulization analysis, wherein we identified 25 modules; ClueGo plug-in was used for the pathway’s enrichment analysis, wherein 37 enriched signalling pathways were obtained. Most of them were associated with human diseases groups, particularly carcinogenesis, inflammation, and infectious diseases. Finally, the analysis of topological characteristic like bottleneck, degree, GO term/pathways analysis, bio-kinetics simulation, molecular docking, and dynamics studies were performed for the selection of key regulatory proteins of curcumin-rewired PIN. The current findings deduce a precise molecular mechanism that curcumin might exert in the system. This comprehensive in-silico study will help to understand how curcumin induces its anti-cancerous, anti-inflammatory, and anti-microbial effects in the human body.

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 translocation of NF-κB p65 and phosphorylation of IκB, which in turn upregulates the expression of important proteins (Glut-1, c-Myc, and Bcl-2) that are involved in glucose metabolism. MUC13 functionally interacts and stabilizes Glut-1 to instigate downstream events responsible for higher glucose uptake in pancreatic cancer cells. Altered MUC13 expression by overexpression and knockdown techniques effectively modulated glucose uptake, lactate secretion, and metastatic phenotypes in pancreatic cancer cells. NF-κB inhibitor, Sulfasalazine, abrogates the MUC13 and Glut-1 interaction, and attenuates events associated with MUC13-induced glucose metabolism. Pancreatic ductal adenocarcinoma (PDAC) patient tissue samples also show a positive correlation between the expression of these two proteins. These results delineate how MUC13 rewire aberrant glucose metabolism to enhance aggressiveness of pancreatic cancer and revealed a novel mechanism to develop newer therapeutic strategies for this exceptionally difficult cancer.

Background 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. Methods 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. Results 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

The therapeutic application of microRNA(s) in the field of cancer has generated significant attention in research. Previous studies have shown that miR-205 negatively regulates prostate cancer cell proliferation, metastasis, and drug resistance. However, the delivery of miR-205 is an unmet clinical need. Thus, the development of a viable nanoparticle platform to deliver miR-205 is highly sought. A novel magnetic nanoparticle (MNP)-based nanoplatform composed of an iron oxide core with poly(ethyleneimine)-poly(ethylene glycol) layer(s) was developed. An optimized nanoplatform composition was confirmed by examining the binding profiles of MNPs with miR-205 using agarose gel and fluorescence methods. The novel formulation was applied to prostate cancer cells for evaluating cellular uptake, miR-205 delivery, and anticancer, antimetastasis, and chemosensitization potentials against docetaxel treatment. The improved uptake and efficacy of formulations were studied with confocal imaging, flow cytometry, proliferation, clonogenicity, Western blot, q-RT-PCR, and chemosensitization assays. Our findings demonstrated that the miR-205 nanoplatform induces significant apoptosis and enhancing chemotherapeutic effects in prostate cancer cells. Overall, these study results provide a strong proof-of-concept for a novel nonviral-based nanoparticle protocol for effective microRNA delivery to prostate cancer cells.

Purpose: Prostate cancer (PrCa) is one of the leading causes of cancer-related deaths among men in the United States. Chemotherapy with docetaxel holds great promise and important therapeutic option for PrCa treatment. However, chemotherapy is often associated with incomplete cell death and leads to persistent senescent phenotype. Such phenotypic cancer cells survive and promotes tumor development, recurrence, and drug resistance. Altogether, targeting these cells can enhance chemotherapy outcomes. In the current study, we established a tannic acid-docetaxel scaffold nanoparticles (TDS NP) platform that allows for facile targeting and inhibition of drug induced senescence in prostate cancer. Methods: TDS NP were prepared by solvent evaporation and extrusion process using a series of tannic acid and docetaxel weight ratios. The scaffold self-assembly formation was determined using a steady-state fluorescence quenching, FT-IR, XRD, DSC, and TGA. The surface and morphological properties of TDS NPs were determined by dynamic light scattering and transmission electron microscopy. The biocompatibility assessment was characterized by hemolysis assay. C4-2 and PC-3 cell lines were used as PrCa model systems for in vitro and in vivo studies. The cellular internalization (in vitro) and accumulation (in vivo) was examined using dye-tagged TDS NPs. The superior in vitro anti-cancer and metastatic potential of TDS NPs were evaluated using proliferation, colony formation, migration, invasion, and immunoblotting assays. The anti-senescence ability of TDS NPs was examined through β-Galactosidase Staining Kit. A PC-3 xenograft mouse model was used to examine its superior therapeutic activity over free docetaxel treatment. Results: A series of physico-chemical analyses confirmed the integrity of TDS NP. An optimized formulation exhibited a spherical shape particle formulation with 124.13 ± 2.16 nm with a negative zeta potential of -14.0 mV. TDS NPs formulation exhibited superior internalization capacity in PrCa cells in a dose- and time-dependent manner. In vitro functional studies confirm superior therapeutic activity of TDS NPs over free docetaxel treatment. Enhanced pro-apoptotic while downregulating anti-apoptotic effects with treatment of TDS NPs in comparison to native drug. A profound inhibition of β-galactosidase activity was noticed with TDS NPs treatment. In vivobiodistribution studies confirm efficient accumulation of TDS NPs in mice. In addition, TDS NPs showed robust antitumor activity against PC-3 xenografts. Such improved activity was correlated with increased inhibition of senescence and induced apoptosis. Conclusion: In summary, we developed a novel tannic acid-docetaxel scaffold nanoparticle formulation that is capable of inhibiting senescence, minimizing drug resistance, and inducing apoptosis in prostate cancer. Citation Format: Prashanth Kumar Bhusetty Nagesh, Pallabita Chowdhury, Elham Hatami, Sonam Kumari, Vivek Kumar Kashyap, Bilal Hafeez, Sheema Khan, Manish Kumar Tripathi, Meena Jaggi, Subhash C. Chauhan, Murali M. Yallapu. Tannic acid-docetaxel scaffold nanoparticles for improved prostate cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3634.

Background: Pancreatic cancer (PanCa) is one of the leading causes of cancer-related mortality in the United States due to very limited therapeutic options. Thus, developing novel therapeutic strategies will help for the management of this disease. We recently identified VERU-111, a novel synthetic molecule which showed potent anti-cancer effect against PanCa via targeting clinically important βIII and βIV tubulin isoforms. In this study, we synthesized and characterized its novel nanoformulation (MNP-VERU) and evaluated its therapeutic effects in vitro and xenograft mouse model. Methods: MNPs were prepared by chemical precipitation method and loaded with VERU-111 using diffusion method. This formulation was characterized for particle size, chemical composition, and drug loading efficiency, using various physico-chemical methods (TEM, FT-IR, DSC, TGA, and HPLC). The internalization of MNP-VERU was achieved after 6 hours incubation with MNP-VERU in PanCa cells. To determine therapeutic efficacy of MNP-VERU, we performed various in vitro (MTS, wound healing, boyden chamber real-time xCELLigence, and apoptosis assays) and in vivo (mouse tumor xenograft) studies using PanCa. Effect of MNP-VERU on various key oncogenic signaling pathways, and miRNAs was evaluated by Western blot, immunohistochemistry (IHC), confocal microscopy, qRT-PCR and in situ hybridization (ISH) analyses respectively. Result: Our novel MNP-VERU formulation provided average size of 110 nm in dynamic light scattering (DLS) and exhibited -8.23 to -11.65 mV zeta potential with an outstanding loading efficiency (94%). Cellular uptake and internalization studies demonstrate that MNP-VERU escape lysosomal degradation, providing efficient endosomal release to cytosol. MNP-VERU showed remarkable anti-cancer potential in various PanCa cells (Panc-1, AsPC-1, HPAF-II, BxPC-3, MiaPaca) and more effectively repressed βIII and βIV tubulin isoforms via restoring the expression of miR-200c. MNP-VERU more effectively suppressed AsPC-1 cells derived xenograft tumors in athymic nude mice. Conclusions: Taken together, our results suggest that MNP-VERU has more anti-cancer potential than free VERU-111 against PanCa. MNP-VERU may reduce the toxicity and improve the bioavailability of free VERU-111 and could be used for the management of PanCa. Citation Format: Vivek K. Kashyap, Bilal B. Hafeez, Qinghui Wang, Neeraj Chauhan, Prashanth K. Nagesh, Murali M. Yallapu, Duane D. Miller, Wei Li, Meena Jaggi, Subhash C. Chauhan. Nanoparticle formulation of VERU 111 for pancreatic cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3619.

Pancreatic cancer (PanCa) is one of the leading causes of cancer-related mortality in the United States due to very limited therapeutic options. Thus, there is an urgent need to develop novel therapeutic strategies for the management of this disease. Paclitaxel (PTX), a natural product derived from the Pacific Yew tree, is an agent typically used in combination therapy for PanCa. Currently, PTX nanoparticles (Abraxane®) along with gemcitabine are in use for the treatment of advanced PanCa. Herein, we have generated and characterized a novel nano-formulation of PTX comprised of PLGA core, stabilized with polyvinyl alcohol (PVA) and coated with poly-L-lysine (PLL). Dynamic light scattering (DLS) characterization indicated that the average particle size of this formulation was approximately 160 nm, and exhibited Zeta potentials of ~ -6.02 mV in 10% serum, along with an outstanding PL loading efficiency. We also evaluated the uptake mechanism of PPNPs in PanCa cells using different endocytosis inhibitors (Genistein, amiloride, nocodazole, chlorpromazine, and methyl beta cyclodextrin). Our results demonstrated that PPNPs were taken up mainly by lipid raft mediated endocytosis pathway in an energy-dependent manner. Next, we evaluated its therapeutic efficacy and underlying molecular mechanisms in human PanCa cells (HPAF-II, Panc1, and MiaPaCa-2) by performing various in vitro experiments. We first performed MTS and colony formation assays to determine the effects of free PTX and PPNPs on growth of PanCa cells. In this experiment, cells were treated with various concentrations of free PTX or abraxane, or PPNPs (2.5-160 nM) for 48 hrs. As a result, the PPNPs formulation showed more therapeutic effect over free abraxane as determined by decrease in cell proliferation and enhanced apoptosis induction in PanCa cells. PPNPs also showed a significant (P Citation Format: Bilal B. Hafeez, Andrew E. Massey, Vivek K. Kashyap, Mohammad Sikander, Advit Shetty, Mehdi Chaib, Hassan Mandil, Mohan Yallapu, Meena Jaggi, Subhash C. Chauhan. Novel nano-formulation of paclitaxel for pancreatic cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-011.

Objective: Cervical cancer is one of the most common and deadly cancers among women worldwide and is associated with persistent Human Papillomavirus (HPV) infection. Human papilloma virus (HPV) expressing E6 and E7 oncoproteins involved in carcinogenesis through their interactions with the p53 and pRB pathways, respectively. Therefore, non-toxic agents that have potential to inhibit the expression of E6 and E7 oncoproteins and their regulated oncogenic signaling pathways could be used in the management of cervical cancer. Microtubule targeting agents including paclitaxel, colchicine and vinca alkaloids are widely used in the treatment of various cancers but most of these agents have toxic side effects and develop chemoresistance. Herein, we investigated the potential anti-cancer effects of a novel tubulin targeting agent (ABI-231) in in vitro and in vivo model systems. Method: ABI-231 ((2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl))- methanone was synthesized in our home institution. Human cervical cancer cells (CaSki and SiHa) were used as in vitro model system. To determine the effect of ABI-231 on cell proliferation, migration and invasion, we performed MTS and wound healing assays. Effect of ABI-231 on the expression of HPV E6/E7 was determined by Western blot, qRT-PCR, and confocal microscopy. Xenograft study was performed to determine the effect of ABI-231 on cervical tumor growth. Results: ABI-231 treatment significantly (P Conclusions: Taken together, our results demonstrate the potential anti-cancer efficacy of ABI-231 in in vivo and in vivo. ABI-231 can be explored as a potent therapeutic agent for the treatment of cervical cancer. Citation Format: Vivek K. Kashyap, Bilal B. Hafeez, Qinghai Wang, Neeraj Chauhan, Prashanth K. Nagesh, Nirnoy Dan, sonam kumari, Shabnam Malik, Saini Setua, Aditya Ganju, Murali M. Yallapu, Duane D. Miller, Wei Li, Meena Jaggi, Subhash C. Chauhan C. Chauhan. ABI-231: A novel small molecule suppresses tumor growth and metastatic phenotypes of cervical cancer cells via targeting HPV E6 and E7 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 679.

Objectives: Docetaxel (Dtx) is the primary choice for the treatment of castrate-resistant prostate cancer (PrCa). Besides its therapeutic benefits, many men with castrate-resistant PCa fail to respond to treatment due to Dtx resistance. There are multiple signaling mechanisms that play pivotal role in the development of Dtx resistance. Seminal reports stated that Tau, highly soluble microtubule-associated protein play a crucial role in Dtx resistance development. Disruption Tau signaling affects its chemoresistance. To revert the drug-resistance and target specific pathway, development of novel and strategic therapies are much needed. In this line, we employed magnetic nanoparticle (MNP) loaded Dtx (MNP-Dtx) to revert the chemo resistance of Dtx in PrCa. Methods: Docetaxel loaded magnetic nanoparticle (MNP-Dtx) formulation is composed of an iron oxide core coated with cyclodextrin (for drug loading) and F127 polymer (for particle stability and chemosensitization). Dtx-resistant PrCa cell line models (PC-3R and DU145R) were developed in our laboratory by repeatedly treating cancer cells in a dose escalation manner for over 24 months. Intracellular drug levels of MNP-Dtx in wild type and drug resistant cancer cells was determined by flow cytometry, TEM and HPLC methods. The superior in vitro anti-cancer activity of MNP-Dtx was examined by MTS, proliferation kinetics, colony formation, immunoblotting and qPCR studies in both wild type and drug resistant PrCa cell lines. The interaction between tau and tubulin studies were assessed through immunoprecipitation studies. Results: MNP-Dtx formulation showed optimal particle size and zeta potential which can efficiently be internalized in PrCa/Dtx resistant PrCa cells. MNP-Dtx exhibited enhanced cellular uptake in drug resistant cell lines over wild type cells in a dose and time dependent manner, with 2 to 3 folds increase. Immunoblot and q PCR studies showed the expression of Tau, whole β tubulin, β tubulin III, β tubulin IV and MDR1 were found to be deregulated in both wild type and resistant cells. To delineate the mechanism of chemosensitization by MNP-Dtx on resistant cells, we performed immunoprecipitation studies, found the expression of Tau was significantly reduced during MNP-Dtx treatments w.r.t control and Dtx. HPLC studies have shown higher amounts of Dtx levels were detected in cells after MNP-Dtx treatments, annotating the sustain drug release ability of MNP nanoformulation. Further, these results were confirmed through tubulin polymerization studies. Conclusion: Overall, sustained drug release of Dtx aided in high intracellular levels of drug, thus facilitating high probability of Dtx-tubulin interaction instead of Tau-tubulin interactions resulting in tubulin fibers stabilization. This promotes Dtx induced apoptosis in wild type and Dtx resistant PrCa cells. This novel therapeutic modality might be effective to treat patients with Dtx resistant PrCa. Citation Format: Prashanth K. B. Nagesh, Pallabita Chowdhury, Elham Hatami, Vivek K. Kashyap, Bilal B. Hafeez, Sheema Khan, Subhash C. Chauhan, Meena Jaggi, Murali M. Yallapu. Docetaxel nanoformulation reverts drug resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4657.

Background: Prostate cancer (PrCa) first manifests as an androgen-dependent disease and can be treated with androgen-deprivation therapy. Despite the initial success of androgen ablation therapy, resistance to anti-androgen therapy displays by progression to hormone refractory (androgen-independent) advanced stage PrCa which is primary cause of patient’s death. Main underlying cause for the onset of hormone refractory cancer is ligand independent activation of AR signaling in PrCa cells. It has been shown that β-catenin acts as a non-androgen activator of AR which enhances AR transactivation in PrCa cells. Thus, identification of agents with excellent pharmacokinetics and pharmacodynamics parameters that can inhibit ligand independent activation of AR signaling might be highly useful for the treatment of advanced stage PrCa. Herein, we identified a synthetic molecule, ormeloxifene (ORM), which efficiently represses β-catenin mediated ligand independent activation of AR signaling, thus, inhibits growth and metastatic features of PrCa cells. Methods: Androgen-refractory but AR positive PrCa cell (C4-2) was used as an in vitro and in vivo model systems. Effect of ORM on AR and PSA protein levels was determined by Western blot analysis. Effect of ORM treatment was analyzed on AR and PSA luciferase activities by transiently transfecting the C4-2 cells by AR and PSA luciferase plasmids. Renilla construct was used as an internal control. C4-2 cells nuclear and cytoplasmic lysates were prepared using Active Motif kit. Immunoprecipitation analysis was performed to determine if ORM inhibits physical interaction of β-catenin with AR. Therapeutic efficacy of ORM was evaluated in cell lines and PrCa xenograft mouse models. Results: ORM dose-dependently (10, 15 and 20 µM) inhibited the protein levels of AR and its downstream target protein PSA. ORM (10 and 20μM) treatment also inhibited AR transactivation as determined by decreased promoter activities of AR and its target gene PSA. ORM (10 and 20μM) treatment inhibited protein levels of nuclear β-catenin and physical interaction of β-catenin with AR in PrCa cells. ORM administration dose- dependently (intra-peritoneal; 100 and/or 500µg/mouse; thrice/week) significantly (P Conclusion: Our study demonstrates that ORM is a potent inhibitor of β-catenin-mediated activation of AR signaling. Based on its safety profile, ORM might be an ideal candidate for repurposing to treat advanced stage PrCa alone or in combination with other therapies. Citation Format: Aditya Ganju, Bilal Bin Hafeez, Mohammed Sikander, Vivek Kumar Kashyap, Murali Mohan Yallapu, Subhash C. Chauhan, Meena Jaggi. Ormeloxifene suppresses the growth of prostate tumor via inhibition of β-catenin induced AR signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2101. doi:10.1158/1538-7445.AM2017-2101

Introduction: Pancreatic cancer (PanCa) is one of the most fatal cancers and is ranked as the fourth common cause of cancer-related deaths among both men and women in the US. The management of PanCa is exceptionally difficult due to the extremely poor response to available chemotherapeutic drugs. Microtubules are dynamic structures composed of α-β-tubulin heterodimers that are essential in cell division and are important targets for several clinical drugs (paclitaxel, docetaxel and vinblastine). However, clinical use of these tubulin-targeting drugs have toxicity and drug resistance issues in cancer patients. Thus, identification of more potent non-toxic inhibitors of β-tubulin is urgently required for cancer therapy purposes. In this study, we have identified a synthetic compound (ABI-231) which is a potent inhibitor of β-tubulin and evaluated its therapeutic efficacy against PanCa in vitro, and in vivo model systems. Methods: ABI-231 ((2-(1H-indol-3-yl)-1H-imidazol-4-yl) (3, 4, 5-trimethoxyphenyl)) - methanone was synthesized and characterized in our department. Effect of ABI-231 on proliferation, migration and invasion of human PanCa cells (ASPC1, HPAFII, and PANC1) was performed by in vitro functional assays (MTS, wound healing, and Boyden chamber migrations). Effect of ABI-231 on the expression of β-tubulin isoforms was determined and compared with other clinical inhibitors of β-tubulin by Western blot, and qRT-PCR. Moreover, the effect of ABI-231 on the expression of β-tubulin III in PanCa cells was determined by confocal microscopy. Therapeutic efficacy of ABI-231 against PanCa was evaluated in an ectopic xenograft mouse model. Results: ABI-231 treatment inhibited cell proliferation, invasion, migration and colony formation abilities of PanCa cells in a dose-dependent manner (1-100 nM) compared to vehicle treated group. Aberrant expression of β-tubulin III is involved in aggressiveness and drug resistance of various type of cancers including PanCa. ABI-231 effectively inhibited the protein levels and mRNA expression of total β-tubulin (TBB), TBB1, TBB2c, TBB3 and TBB4 in PanCa cells via destabilization. Our confocal microscopy results further showed inhibition of β-tubulin in ABI-231 treated PanCa cells. Upregulation of micro RNA 200c (miR-200c) has been shown to inhibit the expression of β-tubulin III in cancer cells. ABI-231 treatment of PanCa cells showed significant (p Conclusion: Taken together, our results suggest that ABI-231 is a potent β-tubulin inhibitor and chemotherapeutic agent which could be used for the treatment of pancreatic cancer. Citation Format: Vivek K. Kashyap, Bilal B. Hafeez, Qinghui Wang, Saini Setua, Andrew Massey, Aditya Ganju, Murali M. Yallapu, Duane D. Miller, Wei Li, Meena Jaggi, Subhash C. Chauhan. Attenuation of pancreatic tumor growth by a small molecule tubulin inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3216. doi:10.1158/1538-7445.AM2017-3216

Objective: High-risk strains of human papillomavirus (HPV), HPV E6/E7 cause cervical cancer (CxCa). Certain underserved populations in the United States, such as American Indian and African American women disproportionately suffer from CxCa compared to their Caucasian counter parts. However, precise etiology and comorbidity factors associated with CxCa health disparity are not fully uncovered. Understanding of these factors at molecular level will entail developing novel strategies to reduce this health disparity. In this study, we have investigated the molecular interplay existing between various comorbidity factors, namely, smoking, alcohol and HIV co-infection on the HPV infectivity which are primarily known for the progression of CxCa. Method: In order to define a molecular association of smoking, alcohol and HIV co-infection with CxCa, Caski and SiHa (HPV infected cervical cancer cells) cells were treated with a smoking carcinogens Benzo[a]Pyrene (BaP) or alcohol (EthOH) or both for different time periods. Effects of these treatment was analyzed on cell proliferation, clonogenicity, cell migration, cell cycle and the expression of HPV E6/E7 was determined by qRT-PCR, immunoblotting and confocal microscopy. The effect of HIV co-infection on the expression of HPV E6/E7 was also investigated by incubating CxCa cells with conditioned medium derived from HIV infected U937 monocytic cells (U1). Additionally, we examined effect of these cofactors on the expression enzymes associated with cellular oxidative stress using immunoblotting and confocal microscopy analyses. Results: Our results show that the exposure of BaP or EthOH or their combination enhances the expression of HPV E6/E7 oncogenes. Additionally, cells treated with BaP and EthOH alone or in combination show higher oncogenic phenotypes as evident by increased cell proliferation, clonogenicity and cell migration and invasion. These cofactors in presence of HIV co-infection also augment the expression of HPVE6/E7 oncogenes. Exposure of these cofactors alter cellular oxidative stress via modulation of the expression of PRDX6 enzyme. Interestingly, curcumin and its nanoparticle formulation (Nano-Cur) effectively inhibit BaP/EthOH induced expression of E6/E7 oncogenes, tumorigenic characteristics of CxCa cells and induce apoptosis. Conclusions: The study suggests a molecular link between smoking, alcohol and HIV infection with HPV infectivity and their potential association with CxCa health disparity. These events however, can be effectively attenuated by curcumin/nano-curcumin treatment, implying its role in CxCa prevention/treatment. This provides hope for developing a feasible approach to effectively reduce CxCa health disparity among underserved populations. Citation Format: Vivek K. Kashyap, Sheema Khan, Mohammad Sikander, Diane M. Maher, Samtosh K. Kumar, Namita Sinha, Murali M. Yallapu, Nadeem Zafar, Meena Jaggi, Subhash C. Chauhan. Comorbidity factors associated with human papillomavirus infectivity: Implications in cervical cancer health disparity. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr IA30.

Objective: High-risk strains of human papillomavirus (HPV), HPV E6/E7 cause cervical cancer (CxCa). Certain underserved populations in the United States, such as American Indian and African American women disproportionately suffer from CxCa compared to their Caucasian counter parts. However, precise etiology and comorbidity factors associated with CxCa health disparity are not fully uncovered. Understanding of these factors at molecular level will entail developing novel strategies to reduce this health disparity. In this study, we have investigated the molecular interplay existing between various comorbidity factors, namely, smoking, alcohol and HIV co-infection on the HPV infectivity which are primarily known for the progression of CxCa. Method: In order to define a molecular association of smoking, alcohol and HIV co-infection with CxCa, Caski and SiHa (HPV infected cervical cancer cells) cells were treated with a smoking carcinogens Benzo[a]Pyrene (BaP) or alcohol (EthOH) or both for different time periods. Effects of these treatment was analyzed on cell proliferation, clonogenicity, cell migration, cell cycle and the expression of HPV E6/E7 was determined by qRT-PCR, immunoblotting and confocal microscopy. The effect of HIV co-infection on the expression of HPV E6/E7 was also investigated by incubating CxCa cells with conditioned medium derived from HIV infected U937 monocytic cells (U1). Additionally, we examined effect of these cofactors on the expression enzymes associated with cellular oxidative stress using immunoblotting and confocal microscopy analyses. Result: Our results show that the exposure of BaP or EthOH or their combination enhances the expression of HPV E6/E7 oncogenes. Additionally, cells treated with BaP and EthOH alone or in combination show higher oncogenic phenotypes as evident by increased cell proliferation, clonogenicity and cell migration andinvasion. These cofactors in presence of HIV co-infection also augment the expression of HPVE6/E7 oncogenes. Exposure of these cofactors alter cellular oxidative stress via modulation of the expression of PRDX6 enzyme. Interestingly, curcumin and its nanoparticle formulation (Nano-Cur) effectively inhibits BaP/EthOH induced expression of E6/E7 oncogenes, growth, migration of CxCa cells and induces apoptosis. Conclusions: The study suggests a molecular link between smoking, alcohol and HIV infection with HPV infectivity and their potential association with CxCa health disparity. These events however, can be effectively attenuated by curcumin/nano-curcumin treatment, implying its role in CxCa prevention/treatment. This provides hope for developing a feasible approach to effectively reduce CxCa health disparity among underserved populations. Citation Format: Vivek K. Kashyap, Sheema Khan, Mohammad Sikander, Diane M. Maher, Santosh Kumar, Namita Sinha, Murali M. Yallapu, Nadeem Zafar, Meena Jaggi, Subhash C. Chauhan. Comorbidity factors associated with human papillomavirus infectivity: Implications in cervical cancer health disparity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1745.