Inhibition of Pancreatic Cancer Cell Viability and Tumor Growth Through Cell...

[Full title: Inhibition of Pancreatic Cancer Cell Viability and Tumor Growth Through Cell Cycle Arrest by an Oral Formulation of Docetaxel DHP23001]

OPEN ACCESS International Journal of Pharmacology ISSN 1811-7775 DOI: 10.3923/ijp.2019.994.1000 Research Article Inhibition of Pancreatic Cancer Cell Viability and Tumor Growth Through Cell Cycle Arrest by an Oral Formulation of Docetaxel DHP 23001 1 Jung Ae Kang, 1 Jung Hyu Sin, 1 Hye Lim Lee, 1 Hye Rim Kim, 1 Sung Hun Kim, 1 Min-Kyoung Kang, 1 A-Ram Yu, 2 Min-Hee Son, 2 Hye-Jin Park and 1 Jae Jun Lee 1 Laboratory Animal Center, Osong Medical Innovation Foundation, 123 Osongsaengmyung-ro, Osong-eup, Heungdeok-gu, 28160 Cheongju-si, Chungbuk, Republic of Korea 2 Pankyo Research Laboratory, Daehwa Pharmaceutical Co., Ltd., C-9 th, Korea Bio Park, 700, Daewangpangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea Abstract Background and Objective: Surgery and radiochemotherapy are the only available regimens for pancreatic cancer treatment However, the therapeutic outcomes in pancreatic cancer appear to be very poor when compared with other cancer subtypes. We investigated the therapeutic potential of an oral formulation of docetaxel (DTX) DHP 23001 in treating pancreatic cancer Materials and Methods: DHP 23001 was prepared for oral administration by dissolving DTX in monoglycerides and oil. The cytotoxicity of DHP 23001 in the human pancreatic cancer cell line AsPC-1 was tested using the 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2 Htetrazolium-5-carboxanilide reduction assay. To test the anti-cancer efficacy of DHP 23001, severe combined immunodeficiency mouse xenograft models were randomized into 4 groups: Group 1, vehicle control (n = 6), group 2, Abraxane (20 mg kg G 1 , n = 6), group 3, low dose DHP 23001 (75 mg kg G 1 , n = 6) and group 4, high dose DHP 23001 (100 mg kg G 1 , n = 6). Tumor size and body weight were measured twice a week for each treatment group. In addition, histological and immunohistochemical analysis were performed on the mice. Results: The results indicate that DHP 23001 treatment significantly suppressed the proliferation of AsPC-1 cells in a dose-dependent manner. DHP 23001 displayed a half-maximal inhibitory concentration of 106 nM. Significant growth inhibition was observed on day 28 in treatment groups 3 and 4 compared to group 1. DHP 23001 significantly reduced the tumor cell growth in the xenograft models by down regulating Ki 67 protein levels. Conclusion: These results suggest the preclinical therapeutic potential of the oral formulation of DTX, DHP 23001 for the treatment of pancreatic cancer Key words: Oral formulation of docetaxel, DHP 23001, anti-tumor, pancreatic cancer, Ki 67 Citation: Jung Ae Kang, Jung Hyu Sin, Hye Lim Lee, Hye Rim Kim, Sung Hun Kim, Min-Kyoung Kang, A-Ram Yu, Min-Hee Son, Hye-Jin Park and Jae Jun Lee, 2019. Inhibition of pancreatic cancer cell viability and tumor growth through cell cycle arrest by an oral formulation of docetaxel DHP 23001. Int. J. Pharmacol., 15: 994-1000 Corresponding Author: Jae Jun Lee, Laboratory Animal Center, Osong Medical Innovation Foundation, 123 Osongsaengmyung-ro, Osong-eup, Heungdeok-gu, 28160 Cheongju-si, Chungbuk, Republic of Korea Tel: +82-42-200-9850 Fax: +82-42-200-9109 Copyright: © 2019 Jung Ae Kang et al. This is an open access article distributed under the terms of the creative commons attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited. Competing Interest: The authors have declared that no competing interest exists Data Availability: All relevant data are within the paper and its supporting information files.

Int. J. Pharmacol., 15 (8): 994-1000, 2019 HO OH OH OH O O O O O O O O O O H NH INTRODUCTION Pancreatic cancer is a malignant tumor that is characterized by the absence of early symptoms and difficulty in diagnosis with blood tests or imaging techniques 1 Furthermore, radical surgery is the only treatment available for pancreatic cancer that completely removes all cancer cells 2 . Despite advances in modern medicine, pancreatic cancer remains a highly malignant disease marked by rapid proliferation and a survival 3 rate of <5%. Early pancreatic cancer can be classified as resectable, small or curable but only a small number of patients can be treated surgically 4 Therefore, it is necessary to study chemotherapeutic methods to improve the prognosis of advanced pancreatic cancer patients The treatment of pancreatic cancer using anti-cancer drugs helps to reduce the size of the tumor, delay cancer progression and prolong survival 5 . Current therapeutic agents such as 5-FU, leucovorin, irinotecan, oxaliplatin, FOLFIRINOX, gemcitabine and nab-paclitaxel are increasing survival rates in some patients 6 . However, the side effects of various anti-cancer drugs administered by injection can be very painful 7,8 . Therefore, the development of oral anti-cancer drugs may provide a convenient alternative to new therapeutic strategies Docetaxel (DTX, Fig. 1) is a chemotherapy medication extensively used for the treatment of a number of different cancer types, including breast cancer, non-small cell lung cancer, advanced stomach cancer, head and neck cancer and metastatic prostate cancer 9,10 . DTX also induces apoptotic cell death by stimulating the phosphorylation of Bcl-2, a protein that inhibits apoptosis 11 . However, intravenous administration of DTX is often associated with acute hypersensitive reactions due to the presence of polysorbate 80 in the formulation, a compound required for drug solubilisation 12-16 . There has been considerable demand for orally bioavailable DTX for chronic treatment regimens. Strategies used to improve the oral bioavailability of DTX include the development of mixed micelle, nanoemulsionand lipid nanocapsule-based formulations 17-19 . Therefore, this study examined the anti-cancer activity of the oral formulation of DTX, DHP 23001 against pancreatic cancer cells both in vitro and in vivo and investigated its potential action mechanism MATERIALS AND METHODS Study duration: This study was carried out from January-April, 2019 at the Osong Medical Innovation Foundation, Laboratory Animal Center, Korea Fig. 1: Chemical structure of docetaxel Molecular weight 807.879 g moL G 1 Kits and reagents: Cell culture reagents were purchased from Gibco BRL (Carlsbad, CA, USA). The anti-Ki 67 antibody was purchased from Santa Cruz Biotechnology (Dallas, TX, USA). The VECTASTAIN ABC Kit was purchased from Vector Laboratories (Burlingame, CA, USA). DHP 23001 was provided by Daehwa Pharmaceutical Co. Ltd. (Hoengseong, Korea). All other reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA) Cell culture and cell viability assay: The AsPC-1 human pancreatic adenocarcinoma cell line was obtained from the American type culture collection (Manassas, VA, USA). Cells were cultured in RPMI 1640 medium supplemented with 10% heat-inactivated fetal bovine serum, 100 U mL G 1 penicillin and 100 µg mL G 1 streptomycin and were maintained at 37 E C in a 5% CO 2 incubator. The cells were seeded at 2×10 6 cells mL G 1 in 96-well plates and incubated for 24 h, then treated with DHP 23001 (12.5, 25, 50 and 100 nM) for 72 h. Cell viability was determined using XTT (2,3-bis-(2-methoxy-4-nitro-5- sulfophenyl)-2 H-tetrazolium-5-carboxanilide) reagent and absorbance measurements at 450 nm. Cell morphology was observed using an inverted microscope connected to a digital camera (IX 71, Olympus, Tokyo, Japan). Percentage cell viability was calculated according to the following Eq 20 : 450 450 Experimental Cell viability (%) 100 Control   Where: Experimental 450 = Absorbance of sample Control 450 = Absorbance of control Pancreatic subcutaneous xenograft model: Severe combined immunodeficiency (SCID, C.B-17-Prkdc scid /NCrKoat, Koatech, Inc., Pyeongtaek, Korea) mice (female, 7 weeks old) were housed under specific pathogen-free conditions according to the guidelines of the Animal Care Committee at the Osong Medical Innovation Foundation (KBIO-IACUC- 995

Int. J. Pharmacol., 15 (8): 994-1000, 2019 150 100 50 0 0 12.5 25 50 100 DHP 23001 (nM) * * * * (b) C ell via bil ity ( % ) 2019-010). On day 0, AsPC-1 cells (2×10 6 cells, 200 L G 1 ) were injected subcutaneously into the right cervical portion of the mice. The mice were randomly divided into 4 groups, group 1 (vehicle control), group 2 (20 mg kg G 1 Abraxane), group 3 (75 mg kg G 1 DHP 23001) and group 4 (100 mg kg G 1 DHP 23001). Groups 1, 3 and 4 received orally administered treatment once every 3 days for 28 days. Group 2 received intravenous treatment once weekly for 28 days. When the tumors had reached an average volume of 75 mm 3 , the body weight and tumor volume of the animals were monitored 3 times/week. The tumor weights were measured on day 28 Tumor volumes were estimated at the end of the experiment by the following formula 21 : 3 Length Width Height Tumor volume (mm ) 2    Histochemical analysis by H and E staining: Animals were sacrificed after 7 days and their brains were recovered, washed in ice-cold phosphate-buffered saline and fixed in 2% formalin Segments from each cerebral hemisphere were embedded in paraffin and serially sectioned into 5 µm slices. The prepared sections were cleared with xylene and hydrated with serial concentrations (70, 80 and 90%) of ethanol. Sections were stained with hematoxylin and eosin (H and E). The nuclei count was analyzed by Image J software Immunohistochemical assay: Immunohistochemistry assays were performed on the sectioned slices to investigate the sections were cleared with xylene and hydrated with a serial concentration of ethanol (70, 80 and 90%). The sections were incubated with specific antibody Ki 67 overnight at 4 E C, followed by anti-rabbit IgG secondary antibody conjugated with HRP. The sections were observed using a microscope (IX 71, Olympus, Tokyo, Japan). The Ki 67-positive cells were analyzed using the Image J software Statistical analysis: The data were analyzed using SPSS software (ver. 20.0, SPSS, Inc., Chicago, IL, USA). Data are presented as the Mean±SD. Statistical analysis was performed using a one-way ANOVA and Tukeyʼs post hoc test. A value of p<0.05 was considered statistically significant RESULTS Inhibitory effect of DHP 23001 on AsPC-1 cell viability: AsPC-1 human pancreatic cancer cells were treated with Fig. 2(a-b): Effect of DHP 23001 on cell viability and morphological changes in AsPC-1 cells (a) AsPC-1 cells were cultured in medium containing various concentrations of DHP 23001 (0, 12.5, 25, 50 and 100 nM) for 72 h and (b) Cell viability was determined using the 2,3-bis-(2-methoxy- 4-nitro-5-sulfophenyl)-2 H-tetrazolium-5-carboxanilide) assay Cell morphologies were imaged using an inverted microscope with x 200 magnification, cell viability is expressed as 100% in the untreated group, data are representative of 3 independent experiments performed in triplicate and expressed as the Mean±SD, *p<0.05 vs. untreated control different drug concentrations (12.5, 25, 50 and 100 nM) for 72 h to investigate the effects of DHP 23001 on cell viability. As shown in Fig. 2, DHP 23001 induced significant morphological changes in AsPC-1 cells (Fig. 2 a). DHP 23001 inhibited the AsPC-1 cell viability in a dose-dependent manner (Fig. 2 b). The IC 50 for DHP 23001 in these cells was 106 nM DHP 23001 regulates tumor growth in AsPC-1 subcutaneous xenograft mice: To determine the anti-tumor effect of DHP 23001 in vivo , we performed a tumor growth assay, H and E staining and immunohistochemical staining in AsPC-1 996 50 nM 100 nM 0 nM 12.5 nM 25 nM (a)

Int. J. Pharmacol., 15 (8): 994-1000, 2019 2000 1500 1000 500 0 1 2 3 4 Groups (c) Tu mo r w ei gh t (m g) ** # ** # 2000 1500 1000 500 0 (b) T umo r vo lume ( m m ) 3 ** # ** # 1 2 3 4 Groups Fig. 3(a-c): Anti-tumor effect of DHP 23001 in pancreatic tumor xenograft mice (a) Representative images of tumor tissues and (b, c) Isolated tumor volumes and weights were measured using a caliper and weight scale (n = 6) AsPC-1 xenograft-bearing mice were treated as follows: Group 1 (vehicle), group 2 (20 mg kg G 1 Abraxane), group 3 (75 mg kg G 1 DHP 23001), group 4 (100 mg kg G 1 DHP 23001), mice were euthanized on day 28 and tumor tissues were isolated, data are expressed as the Mean±SD, **p<0.001 vs group 1, # p<0.05 vs. group 1 subcutaneous xenograft-bearing mouse models. For the tumor growth assay, the tumor size, volume and weight were measured for tumor tissues in AsPC-1 subcutaneous xenograft-bearing mice. As shown in Fig. 3, the tumors in group 2 did not change in size compared with group 1, whereas group 3 and 4 experienced a significant reduction in tumor size (Fig. 3 a). The tumor volumes of groups 1, 2, 3 and 4 were 1792.3±72.4, 1321.5±110.3, 730.4±61.2 and 654.2±100.1 mm 3 , respectively (Fig. 3 b). The tumor weights of groups 1, 2, 3 and 4 were 1792.3±90.2, 1555.6±126.9, 908.3±84.4 and 849.9±100.1 mg, respectively (Fig. 3 c). Next, to confirm whether DHP 23001 reduced the tumor growth, anti-cancer efficacy was defined by analyzing changes in the numbers and morphology of nuclei in H and E-stained tissues. As shown in Fig. 4, the administration of DHP 23001 significantly reduced the number of cells in pancreatic tumor tissues. The nuclei numbers of groups 1, 2, 3 and 4 were 465.3±27.63, 401.7±15.89, 209.0±18.0 and 189.3±20.53, respectively. Next, through immunochemical staining, we investigated whether DHP 23001 regulates the cell cycle for tumor tissues in AsPC 1-xenograft mice. To determine whether DHP 23001 regulates the cell cycle, we quantified Ki 67 protein expression levels through immunostaining. The intensity in group 1 was designated as 100%. As shown in Fig. 5, the protein expressions of Ki 67 in groups 2, 3 and 4 were 48.8±1.7, 28.5±4.6 and 25.8±2.9, respectively DHP 23001 prevents the development of drug resistance: Chemotherapy failure is associated with multidrug resistance, wherein anti-cancer efficacy is lost after repeated exposure to chemotherapy and changes in the patient's weight 22 . As shown in Fig. 6, administration of DHP 23001 did not change the body weight in AsPC-1 subcutaneous xenograft mice DISCUSSION This study demonstrates that the oral formulation of DTX, DHP 23001, inhibits AsPC-1 cell growth and tumorigenesis in the immunodeficiency mouse xenograft models through the regulation of tumor growth. Furthermore, Ki 67 activity was attenuated by DHP 23001 on tumorigenic pancreatic tissues in mice. Chemotherapy uses anti-cancer drugs to perform 997

Int. J. Pharmacol., 15 (8): 994-1000, 2019 600 400 200 0 * (b) N ucl ei co unt ** # ** # 1 2 3 4 Groups 150 100 50 0 1 Groups * (b) R elat iv e exp re ssi on o f K i 6 7 (% ) # ** # ** 2 3 4 Fig. 4(a-b): Histological analysis (a) H and E-stained tissues and (b) Bar graph was obtained from panel A, nucleic counts were quantified using imageJ software (n = 4) Red arrows indicate damaged cells, data are expressed as the Mean±SD, *p<0.05 vs. untreated control, **p<0.001 vs. group 1, # p<0.05 vs. group 2 Fig. 5(a-b): Immunohistochemical analysis of Ki 67 expression in a pancreatic cancer xenograft model (a) Expression of Ki 67 on the tumor and (b) The graph was obtained from panel A Ki 67-positive cells. The expression of Ki 67 relative to group 1 (%) Mice were euthanized on day 28 of treatment, isolated tumors were fixed in 4% formalin and sectioned, red arrows within black dotted lines indicate Ki 67-position cells, data are expressed as the Mean±SD, *p<0.05 vs. untreated control, **p<0.001 vs. group 1, # p<0.05 vs. group 2 998 (a) 1 2 3 4 Groups (a) 1 2 3 4 Groups

Int. J. Pharmacol., 15 (8): 994-1000, 2019 25 20 15 10 5 0 0 3 6 9 12 15 18 21 25 28 Days Bo dy w ei gh t (g) Group 1 Group 2 Group 3 Group 4 Fig. 6: Body weight over the study period AsPC-1 cells (2×106 cells mL G 1 ) were injected subcutaneously into mice, group 1 (vehicle), group 2 (20 mg kg G 1 Abraxane), group 3 (75 mg kg G 1 DHP 23001), group 4 (100 mg kg G 1 DHP 23001), groups 1, 3 and 4 were orally administered treatment once every 3 days for 28 days, group 2 received intravenously injected treatment once weekly for 28 days, body weights were measured 3 times/week, data are expressed as the Mean±SD systemic treatments on cancer cells, regulate cell cycles and induce apoptosis 23 . DTX is a plant alkaloid that interferes with microtubule function and thereby impedes cell division Recently, the results of multiple clinical studies involving cell cycle control research have reported DTX as an anticancer mechanism 24 . However, DTX is an injectable drug that causes side effects and discomfort in chemotherapy for various patients with cancer and there is a need for improvement Nurgali et al 25 reported that patients might experience side effects that could prevent other important treatment strategies involving chemotherapy from being administered Therefore, these results suggest a method for treating pancreatic cancer with orally administered DHP 23001 as a way of improving quality of life and prolonging the survival of patients Although DTX is administered as an injectable drug, which causes side effects and discomfort, it has nonetheless been used in clinical trials for various patients with cancer 26 . In many clinical studies, the use of DTX injections has been reported to result in hematological or non-hematologic side effects, such as instigating peripheral edema, pleural fluid, pleural ascites and weight gain 27 . Therefore, Yang et al 28 suggested that the most important issue to consider in chemotherapy is the development of anticancer drugs through the inhibition of drug resistance. For example, Abraxane is an injectable form of paclitaxel, a cytotoxic anti-cancer agent, where the drug is bound to albumin as a delivery system by way of nab-technology. Abraxane has a limited effect on normal cells compared to unbound paclitaxel, thereby allowing the incorporation of additional therapeutic agents to reach cancer cells 29 In this study, the anti-cancer effects of DHP 23001 on pancreatic cancer cells was compared with that of Abraxane. The results indicate that DHP 23001 administered orally every 3 days was more effective than once-weekly Abraxane treatment (Fig. 3, 4 and 5). Interestingly, since no change in body weight was observed during oral drug treatment, there were no concerns regarding toxicity or resistance (Fig. 5). These results suggest that oral administration of DHP 23001 may eliminate side effects even in the long-term treatment of patients with pancreatic cancer CONCLUSION Taken together, these results suggest that DHP 23001 inhibits pancreatic cancer cell growth through cell cycle arrest, which consequently results in a decrease in both tumor size and weight. This study indicates that DHP 23001 is a potential candidate for the treatment of malignant pancreatic cancer. Further studies are warranted to address whether combined therapies are feasible for clinical application of the oral formulation of anti-cancer drugs SIGNIFICANCE STATEMENT This study demonstrates the anti-tumor effects of the oral formulation of DTX, DHP 23001, against pancreatic tumor cell growth by regulating the cell cycle. Furthermore, treatment with DHP 23001 did not result in a change in the body weight of mice during the 28 days chemotherapy period. Therefore, DHP 23001 is an antitumor drug candidate that is beneficial for the treatment of patients with pancreatic cancer. This study will assist researchers in the development of new drugs that reduce the side effects of anticancer drugs ACKNOWLEDGMENT This research was supported by a grant from the Osong Medical Cluster R and D Project funded by the Republic of Koreaʼs Ministry of Health and Welfare (grant number HO 16 C 0002 and HO 15 C 0001) REFERENCES 1 Chari, S.T., K. Kelly, M.A. Hollingsworth, S.P. Thayer and D.A. Ahlquist, 2015. Early detection of sporadic pancreatic cancer: Summative review. Pancreas, 44: 693-712 999

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Toxicity, Chemotherapy, Vehicle, Therapeutic agent, Penicillin, Survival, Pain management, Statistical analysis, Quality of life, Oral administration, Clinical trial, Statistically Significant, Weight gain, Spss software, Pancreatic Cancer, In vitro, One-way ANOVA, Anti-cancer activity, Clinical application, Apoptosis, Drug resistance, Multidrug resistance, Vehicle control, Body weight, Intravenous administration, Cell viability, Dose-dependent manner, Body weight change, Inhibitory effect, Cell morphology, IC50, Oral bioavailability, Albumin, Cell viability assay, Tumorigenesis, In vivo, Cell division, Tumor Size, Digital camera, Hematological Side Effects, Polysorbate 80, Histological analysis, Absorbance measurement, Paclitaxel, Pleural fluid, Fetal bovine serum, Side effect, Ethanol, Cell cycle arrest, Anti-tumor effect, Tumor volume, Tumor weight, Cell cycle, Tumor growth inhibition, Untreated control, Streptomycin, Intravenous treatment, Apoptotic cell death, XTT assay, Combined therapies, New Drug, Immunohistochemical assay, Percentage cell viability, Animal Care Committee, Histochemical analysis, Normal cells, Cell cycle control, Protein expression, Anti-Cancer Drug, Tumor tissue, Hypersensitive reaction, Pathogen-free conditions, Tukey's post-hoc test, Inverted microscope, RPMI 1640 medium, Paraffin embedding, Radical surgery, Histone deacetylase inhibitor, Cerebral hemisphere, Cancer cell, Immunostaining, Docetaxel, Peripheral edema, Damaged cells, Xylene, Plant Alkaloid, Abraxane, H and E staining, Eosin, Image J software, Weight scale, Chemotherapy failure, Injectable drug, Advanced pancreatic cancer.