Related articles in JMB
Research article | 2020-02-28
Kanakugiol, a Compound Isolated from Lindera erythrocarpa, Promotes Cell Death by Inducing Mitotic Catastrophe after Cell Cycle ArrestJintak Lee , Hyun-Woo Chun , Thu-Huyen Pham , Jae-Hwan Yoon , Jiyon Lee , Myoung-Kwon Choi , Hyung-Won Ryu , Sei-Ryang Oh , Jaewook Oh and Do-Young YoonResearch article | 2018-06-28
Siamese Crocodile White Blood Cell Extract Inhibits Cell Proliferation and Promotes Autophagy in Multiple Cancer Cell LinesSanti Phosri , Nisachon Jangpromma , Leng Chee Chang , Ghee T. Tan , Supakit Wongwiwatthananukit , Surachai Maijaroen , Preeyanan Anwised , Wisarut Payoungkiattikun and Sompong KlaynongsruangResearch article | 2018-06-28
Research articleMolecular and Cellular Microbiology (MCM) | Clinical Microbiology and Biomedical Sciences
Combination of Doxorubicin with Gemcitabine-Incorporated GQuadruplex Aptamer Showed Synergistic and Selective Anticancer Effect in Breast Cancer CellsMili Joshi , Jong-Soo Choi , Jae-Won Park and Kyung-Oh Doh *
Department of Physiology, College of Medicine, Yeungnam University, Daegu 42415 Republic of Korea.Received: July 12, 2019; Accepted: September 3, 2019
J. Microbiol. Biotechnol. 2019; 29(11): 1799-1805
Published November 28, 2019
Copyright © The Korean Society for Microbiology and Biotechnology.
AbstractDoxorubicin (DOX) is one of the most effective anticancer agents used for the treatment of multiple cancers; however, its use is limited by its short half-life and adverse drug reactions, especially cardiotoxicity. In this study, we found that the conjugate of DOX with APTA12 (Gemcitabine incorporated G-quadruplex aptamer) was significantly more cancer selective and cytotoxic than DOX. The conjugate had an affinity for nucleolin, with higher uptake and retention into the cancer cells than those of DOX. Further, it was localized to the nucleus, which is the target site of DOX. Owing to its mechanism of action, DOX has the ability to intercalate into the nucleotides thus making it a suitable drug to form a conjugate with cancer selective aptamers such as APTA12. The conjugation can lead to selectively accumulate in the cancer cells thus decreasing its potential nonspecific as well as cardiotoxic side effects. The aim of this study was to prepare a conjugate of DOX with APTA12 and assess the chemotherapeutic properties of the conjugate specific to cancer cells. The DOX-APTA12 conjugate was prepared by incubation and its cytotoxicity in MCF-10A (non-cancerous mammary cells) and MDA-MB-231 (breast cancer cells) was assessed. The results indicate that DOX-APTA12 conjugate is a potential option for chemotherapy especially for nucleolin expressing breast cancer with reduced doxorubicin associated side effects.
KeywordsG-Quadruplex aptamer, selective Anticancer Therapy, Doxorubicin, breast cancer, gemcitabine
- Chaires JB, Herrera JE, Waring MJ. 1990. Preferential binding of daunomycin to 5’TACG and 5’TAGC sequences revealed by footprinting titration experiments. Biochemistry 29: 6145-6153.
- Singal PK, Siveski-Iliskovic N, Hill M, Thomas TP, Li T. 1995. Combination therapy with probucol prevents adriamycininduced cardiomyopathy. J. Mol. Cell. Cardiol. 27: 1055-1063.
- Fridrik MA, Jaeger U, Petzer A, Willenbacher W, Keil F, Lang A, et al. 2016. Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diffuse large B-cell lymphoma: A randomised phase-III study from the Austrian Cancer Drug Therapy Working Group [Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT](NHL-14). Eur. J. Cancer 58: 112-121.
- Bates PJ, Laber DA, Miller DM, Thomas SD, Trent JO. 2009. Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer. Exp. Mol. Pathol. 86: 151-164.
- Gold L. 1995. Oligonucleotides as research, diagnostic, and therapeutic agents. J. Biol. Chem. 270: 13581-13584.
- Bates PJ, Reyes-Reyes EM, Malik MT, Murphy EM, O’toole MG, Trent JO. 2017. G-quadruplex oligonucleotide AS1411 as a cancer-targeting agent: Uses and mechanisms. Biochim. Biophys. Acta Gen. Subj. 1861: 1414-1428.
- Rosenberg JE, Bambury RM, Van Allen EM, Drabkin HA, Lara PN, Harzstark AL, et al. 2014. A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma. Invest. New Drugs 32: 178-187.
- Park JY, Cho YL, Chae JR, Moon SH, Cho WG, Choi YJ, et al. 2018. Gemcitabine-incorporated G-Quadruplex aptamer for targeted drug delivery into pancreas cancer. Mol. Ther. Nucleic Acids 12: 543-553.
- Reyes-Reyes EM, Teng Y, Bates PJ. 2010. A new paradigm for aptamer therapeutic AS1411 action: uptake by macropinocytosis and its stimulation by a nucleolin-dependent mechanism. Cancer Res. 70: 817-829.
- Fonseca NA, Rodrigues AS, Rodrigues-Santos P, Alves V, Gregorio AC, Valerio-Fernandes A, et al. 2015. Nucleolin overexpression in breast cancer cell sub-populations with different stem-like phenotype enables targeted intracellular delivery of synergistic drug combination. Biomaterials 69: 76-88.
- Qiu W, Zhou F, Zhang Q, Sun X, Shi X, Liang Y, et al. 2013. Overexpression of nucleolin and different expression sites both related to the prognosis of gastric cancer. APMIS 121: 919-925.
- Berger CM, Gaume X, Bouvet P. 2015. The roles of nucleolin subcellular localization in cancer. Biochimie 113: 78-85.
- Rivera E, Valero V, Arun B, Royce M, Adinin R, Hoelzer K, et al. 2003. Phase II study of pegylated liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancer. J. Clin. Oncol. 21: 3249-3254.
- Ueno H, Kiyosawa K, Kaniwa N. 2007. Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy? Br. J. Cancer 97: 145-151.
- Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W. 1991. Action of 2’, 2’-difluorodeoxycytidine on DNA synthesis. Cancer Res. 51: 6110-6117.
- Maréchal R, Mackey JR, Lai R, Demetter P, Peeters M, Polus M, et al. 2009. Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin. Cancer Res. 15: 2913-2919.
- Mackey JR, Mani RS, Selner M, Mowles D, Young JD, Belt JA, et al. 1998. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res. 58: 4349-4357.
- Vrignaud S, Benoit J-P, Saulnier P. 2011. Strategies for the nanoencapsulation of hydrophilic molecules in polymerbased nanoparticles. Biomaterials 32: 8593-8604.
- Amrutkar M, Gladhaug I. 2017. Pancreatic cancer chemoresistance to gemcitabine. 9(11). pii: E157. doi: 10.3390/cancers9110157.
- Li L, Xiang D, Shigdar S, Yang W, Li Q, Lin J, et al. 2014. Epithelial cell adhesion molecule aptamer functionalized PLGA-lecithin-curcumin-PEG nanoparticles for targeted drug delivery to human colorectal adenocarcinoma cells. Int. J. Nanomedicine 9: 1083-1096.
- Zhou W, Zhou Y, Wu J, Liu Z, Zhao H, Liu J, et al. 2014. Aptamer-nanoparticle bioconjugates enhance intracellular delivery of vinorelbine to breast cancer cells. J. Drug Target. 22: 57-66.
- Ray P, Cheek MA, Sharaf ML, Li N, Ellington AD, Sullenger BA, et al. 2012. Aptamer-mediated delivery of chemotherapy to pancreatic cancer cells. Nucleic Acid Ther. 22: 295-305.
- Shahidi-Hamedani N, Shier WT, Moghadam Ariaee F, Abnous K, Ramezani M. 2013. Targeted gene delivery with noncovalent electrostatic conjugates of sgc-8c aptamer and polyethylenimine. J. Gene. Med. 15: 261-269
- Bagalkot V, Farokhzad OC, Langer R, Jon S. 2006. An aptamer–doxorubicin physical conjugate as a novel targeted drug-delivery platform. Angew. Chem. Int. Ed. Engl. 45: 8149-8152.
- Vogus DR, Evans MA, Pusuluri A, Barajas A, Zhang M, Krishnan V, et al. 2017. A hyaluronic acid conjugate engineered to synergistically and sequentially deliver gemcitabine and doxorubicin to treat triple negative breast cancer. J. Control. Release 267: 191-202.
- Vogus DR, Pusuluri A, Chen R, Mitragotri S. 2018. Schedule dependent synergy of gemcitabine and doxorubicin: Improvement of in vitro efficacy and lack of in vitro-in vivo correlation. Bioeng. Trans. Med. 3: 49-57.
- Ling Y-H, El-Naggar AK, Priebe W, Perez-Soler R. 1996. Cell cycle-dependent cytotoxicity, G2/M phase arrest, and disruption of p34cdc2/cyclin B1 activity induced by doxorubicin in synchronized P388 cells. Mol. Pharmacol. 49: 832-841.
- Matthews DJ, Yakes M, Chen J, Tadano M, Bornheim L, Clary DO, et al. 2007. Pharmacological abrogation of S-phase checkpoint enhances the anti-tumor activity of gemcitabine in vivo. Cell Cycle 6: 104-110.
- Xu X, Hamhouyia F, Thomas SD, Burke TJ, Girvan AC, McGregor WG, et al. 2 001. I nhibition o f DNA replication and induction of S phase cell cycle arrest by G-rich oligonucleotides. J. Biol. Chem. 276: 43221-43230.
- Hovanessian AG, Soundaramourty C, El Khoury D, Nondier I, Svab J, Krust B. 2010. Surface expressed nucleolin is constantly induced in tumor cells to mediate calciumdependent ligand internalization. PLoS One 5: e15787.