Доступ предоставлен для: Guest
Портал Begell Электронная Бибилиотека e-Книги Журналы Справочники и Сборники статей Коллекции
Critical Reviews™ in Oncogenesis
SJR: 0.631 SNIP: 0.503 CiteScore™: 2.2

ISSN Печать: 0893-9675
ISSN Онлайн: 2162-6448

Critical Reviews™ in Oncogenesis

DOI: 10.1615/CritRevOncog.2019031202
pages 179-190

Current Perspectives of Exosomes as Therapeutic Targets and Drug Delivery Vehicles for Pancreatic Cancer

L. Srinivas
Institute of Pharmacy, GITAM (Deemed to be University), Visakhapatnam, India
Deepthi S
Institute of Pharmacy, GITAM (Deemed to be University), Visakhapatnam, India
Deepak KGK
Cancer Biology Lab, Department of Biochemistry and Bioinformatics, Institute of Science, GITAM (Deemed to be University), Visakhapatnam, India
Rama Rao Malla
Cancer Biology Lab, Department of Biochemistry and Bioinformatics, GIS, GITAM (Deemed to be University), Visakhapatnam, India

Краткое описание

The ever-growing interest in exosomes research is mainly due to their potential applications in health and disease, especially in therapy and diagnosis. To explore the applications of exosomes in the clinical setting, we must understand their characteristics at the molecular levels. Furthermore, exosomes are cell and function specific; therefore, we must ascertain the molecular mechanisms of their biogenesis, cellular recognition, and uptake. In the recent past, engineered exosomes and exosome mimetics have been the subject of active research. However, critical facets of the biology of engineered exosomes and exosome mimetics remain unknown. This review presents our current understanding of the potential role of engineered exosomes and exosome mimetics in diagnosis, prognosis, monitoring of treatment, as well as drug delivery. We also present recent updates on the exosome signature, its role in pancreatic cancer progression, and applications in the delivery of natural therapeutics and RNAi molecules and in the immune response. Lastly, we discuss future prospects and challenges of exosomes in translational studies.


  1. Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci. 2018;75:193-208.

  2. Thery C. Exosomes: secreted vesicles and intercellular communications. F1000 Biol Rep. 2011;3:15.

  3. Maas SLN, Breakefield XO, Weaver AM. Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol. 2017;27:172-88.

  4. Zappulli V, Friis KP, Fitzpatrick Z, Maguire CA, Breakefield XO. Extracellular vesicles and intercellular communication within the nervous system. J Clin Invest. 2016;126:1198-207.

  5. Maia J, Caja S, Strano Moraes MC, Couto N, Costa-Silva B. Exosome-based cell-cell communication in the tumor microenvironment. Front Cell Dev Biol. 2018;6:18.

  6. Rashed MH, Bayraktar E, Helal GK, Abd-Ellah M, Amero P, Chavez-Reyes A, Rodriguez-Aguayo C. Exosomes: from garbage bins to promising therapeutic targets. Int J Mol Sci. 2017;18.

  7. Kalra H, Drummen GP, Mathivanan S. Focus on extracellular vesicles: introducing the next small big thing. Int J Mol Sci. 2016;17:170.

  8. Rajagopal C, Harikumar KB. The origin and functions of exosomes in cancer. Front Oncol. 2018;8:66.

  9. Oves M, Qari HA, Felemban NM, Khan AAP, Rehan M, Tabrez S, Ahmed F, Haque A, Khan MS, Khan JM. Exosomes: a paradigm in drug development against cancer and infectious diseases. J Nanomater. 2018;2018.

  10. Lin J, Li J, Huang B, Liu J, Chen X, Chen XM, Xu YM, Huang LF, Wang XZ. Exosomes: novel biomarkers for clinical diagnosis. Sci World J. 2015;2015: 657086.

  11. Bunggulawa EJ, Wang W, Yin T, Wang N, Durkan C, Wang Y, Wang G. Recent advancements in the use of exosomes as drug delivery systems. J Nanobiotechnol. 2018;16:81.

  12. Livshits MA, Khomyakova E, Evtushenko EG, Lazarev VN, Kulemin NA, Semina SE, Generozov EV, Govorun VM. Isolation of exosomes by differential centrifugation: theoretical analysis of a commonly used protocol. Sci Rep. 2015;5: 17319.

  13. Helwa I, Cai J, Drewry MD, Zimmerman A, Dinkins MB, Khaled ML, Seremwe M, Dismuke WM, Bieberich E, Stamer WD, Hamrick MW. A comparative study of serum exosome isolation using differential ultracentrifugation and three commercial reagents. PLoS One. 2017 Jan 23;12(1):e0170628.

  14. Yakimchuk K. Exosomes: isolation and characterization methods and specific markers. Mater Methods. 2015;5:1450-3.

  15. Contreras-Naranjo JC, Wu HJ, Ugaz VM. Microfluidics for exosome isolation and analysis: enabling liquid biopsy for personalized medicine. Lab Chip. 2017;17: 3558-77.

  16. Deregibus MC, Figliolini F, D'Antico S, Manzini PM, Pasquino C, De Lena M, Tetta C, Brizzi MF, Camussi G. Charge-based precipitation of extracellular vesicles. Int J Mol Med. 2016;38:1359-66.

  17. Evans R, Martin KH, Moses BS, Slone WL, Hare I, Piktel D, Thomas P, Gibson LF. Modeling the bone marrow microenvironment's influence on leukemic disease. Transl Biomed. 2015;6.

  18. Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protocols Cell Biol. 2006;30(1):3-22; chapter 3, unit 3.22.

  19. Kang H, Kim J, Park J. Methods to isolate extracellular vesicles for diagnosis. Micro Nano Systems Lett. 2017;5:15.

  20. Zeringer E, Barta T, Li M, Vlassov AV. Strategies for isolation of exosomes. Cold Spring Harb Protoc. 2015;2015:319-23.

  21. Logozzi M, De Milito A, Lugini L, Borghi M, Calabro L, Spada M, Perdicchio M, Marino ML, Federici C, Iessi E, Brambilla D. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS One. 2009 Apr 17;4(4):e5219.

  22. Lee K, Shao H, Weissleder R, Lee H. Acoustic purification of extracellular microvesicles. ACS Nano. 2015;9: 2321-27.

  23. Davies RT, Kim J, Jang SC, Choi EJ, Gho YS, Park J. Microfluidic filtration system to isolate extracellular vesicles from blood. Lab Chip. 2012;12:5202-10.

  24. Cai S, Luo B, Jiang P, Zhou X, Lan F, Yi Q, Wu Y. Immuno-modified superparamagnetic nanoparticles via host-guest interactions for high-purity capture and mild release of exosomes. Nanoscale. 2018;10(29):14280-9.

  25. Dragovic RA, Gardiner C, Brooks AS, Tannetta DS, Ferguson DJ, Hole P, Carr B, Redman CW, Harris AL, Dobson PJ, Harrison P, Sargent IL. Sizing and phenotyping of cellular vesicles using nanoparticle tracking analysis. Nanomedicine. 2011;7:780-8.

  26. Lim J, Yeap SP, Che HX, Low SC. Characterization of magnetic nanoparticle by dynamic light scattering. Nanoscale Res Lett. 2013;8:381.

  27. Graham MD. The Coulter principle: Imaginary origins. Cytometry. 2013;83:1057-61.

  28. Petersen KE, Manangon E, Hood JL, Wickline SA, Fernandez DP, Johnson WP, Gale BK. A review of exosome separation techniques and characterization of B16-F10 mouse melanoma exosomes with AF4-UV-MALS-DLS-TEM. Anal Bioanal Chem. 2014;406:7855.

  29. Sharma S, Gillespie BM, Palanisamy V, Gimzewski JK. Quantitative nanostructural and single-molecule force 43. spectroscopy biomolecular analysis of human-saliva-derived exosomes. Langmuir. 2011;27:14394-400.

  30. Aras O, Shet A, Bach RR, Hysjulien JL, Slungaard A, Hebbel RP, Escolar G, Jilma B, Key NS. Induction of microparticle- and cell-associated intravascular tissue factor in human endotoxemia. Blood. 2004;103:4545-53.

  31. Schachermeyer S, Ashby J, Zhong W. Advances in field-flow fractionation for the analysis of biomolecules: instrument design and hyphenation. Anal Bioanal Chem. 2012;404:1151-58.

  32. Smith ZJ, Lee C, Rojalin T, Carney RP, Hazari S, Knudson A, Lam K, Saari H, Ibanez EL, Viitala T, Laaksonen T. Single exosome study reveals subpopulations distributed among cell lines with variability related to membrane content. J Extracellular Vesicles. 2015 Jan 1;4(1):28533.

  33. He M, Crow J, Roth M, Zeng Y, Godwin AK. Integrated immunoisolation and protein analysis of circulating exosomes using microfluidic technology. Lab Chip. 2014;14:3773-80.

  34. Ferracin M, Negrini M. Quantification of circulating MICRORNAS by droplet digital PCR. Methods Mol Biol (Clifton, NJ). 2018;1768:445-57.

  35. Higginbotham JN, Zhang Q, Jeppesen DK, Scott AM, Manning HC, Ochieng J, Franklin JL, Coffey RJ. Identification and characterization of EGF receptor in individual exosomes by fluorescence-activated vesicle sorting. J Extracellular Vesicles. 2016;5:29254.

  36. McKelvey KJ, Powell KL, Ashton AW, Morris JM, McCracken SA. Exosomes: mechanisms of uptake. J Circ Biomarkers. 2015;4:7.

  37. Shanmuganathan M, Vughs J, Noseda M, Emanueli C. Exosomes: basic biology and technological advancements suggesting their potential as ischemic heart disease therapeutics. Front Physiol. 2018;9:1159.

  38. He C, Zheng S, Luo Y, Wang B. Exosome theranostics: biology and translational medicine. Theranostics. 2018;8:237-55.

  39. Aguirre TA, Teijeiro-Osorio D, Rosa M, Coulter IS, Alonso MJ, Brayden DJ. Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials. Adv Drug Delivery Rev. 2016;106:223-41.

  40. Kamerkar S, LeBleu VS, Sugimoto H, Yang S, Ruivo CF, Melo SA, Lee JJ, Kalluri R. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature. 2017;546:498-503.

  41. Mendt M, Kamerkar S, Sugimoto H, McAndrews KM, Wu CC, Gagea M, Yang S, Blanko EV, Peng Q, Ma X, Marszalek JR. Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight. 2018 Apr 19;3(8).

  42. Whiteside TL. Therapeutic targeting of oncogenic KRAS in pancreatic cancer by engineered exosomes. Trans Cancer Res. 2017;6: S1406-s8.

  43. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature Biotechnol. 2011;29:341-45.

  44. Liu Y, Li D, Liu Z, Zhou Y, Chu D, Li X, Jiang X, Hou D, Chen X, Chen Y, Yang Z. Targeted exosome-mediated delivery of opioid receptor Mu siRNA for the treatment of morphine relapse. Sci Rep. 2015 Dec 3;5:17543.

  45. Ohno S, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, Fujita K, Mizutani T, Ohgi T, Ochiya T, Gotoh N, Kuroda M. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther. 2013;21:185-91.

  46. Limoni SK, Moghadam MF, Moazzeni SM, Gomari H, Salimi F. Engineered exosomes for targeted transfer of siRNA to HER2 positive breast cancer cells. Appl Biochem Biotechnol. 2019 Jan 15;187(1):352-64.

  47. Antimisiaris S, Mourtas S, Marazioti A. Exosomes and exosome-inspired vesicles for targeted drug delivery. Pharmaceutics. 2018 Dec;10(4):218.

  48. Yoon J, Jo W, Jeong D, Kim J, Jeong H, Park J. Generation of nanovesicles with sliced cellular membrane fragments for exogenous material delivery. Biomaterials. 2015;59:12-20.

  49. Jang SC, Kim OY, Yoon CM, Choi DS, Roh TY, Park J, Nilsson J, Lotvall J, Kim YK, Gho YS. Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemo therapeutics to malignant tumors. ACS Nano. 2013;7:7698-710.

  50. Lunavat TR, Jang SC, Nilsson L, Park HT, Repiska G, Lasser C, Nilsson JA, Gho YS, Lotvall J. RNAi delivery by exo some-mimetic nanovesicles-implications for targeting c-Myc in cancer. Biomaterials. 2016;102:231-38.

  51. Tai YL, Chen KC, Hsieh JT, Shen TL. Exosomes in cancer development and clinical applications. Cancer Sci. 2018;109:2364-74.

  52. Whiteside TL. Tumor-derived exosomes and their role in cancer progression. Adv Clin Chem. 2016;74:103-41.

  53. Zhang C, Ji Q, Yang Y, Li Q, Wang Z. Exosome: function and role in cancer metastasis and drug resistance. Technol Cancer Res Treatment. 2018;17: 1533033818763450.

  54. Sung BH, Weaver AM. Exosome secretion promotes chemotaxis of cancer cells. Cell Adh Migr. 2017;11:187-95.

  55. Falasca M, Kim M, Casari I. Pancreatic cancer: current research and future directions. Biochimica Biophysica Acta. 2016;1865:123-32.

  56. Cui GH, Wu J, Mou FF, Xie WH, Wang FB, Wang QL, Fang J, Xu YW, Dong YR, Liu JR, Guo HD. Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice. FASEB J. 2017 Sep 69. 27;32(2):654-68.

  57. Lamichhane TN, Leung CA, Douti LY, Jay SM. Ethanol induces enhanced vascularization bioactivity of endothelial cell-derived extracellular vesicles via regulation of microRNAs and long non-coding RNAs. Sci Rep. 2017 Oct 23;7(1):13794.

  58. Klein AP. Genetic susceptibility to pancreatic cancer. Mol Carcinogen. 2012;51:14-24.

  59. Neesse A, Michl P, Frese KK, Feig C, Cook N, Jacobetz MA, Lolkema MP, Buchholz M, Olive KP, Gress TM, 71. Tuveson DA. Stromal biology and therapy in pancreatic cancer. Gut. 2011;60:861-68.

  60. Stefanius K, Servage K, de Souza Santos M, Gray HF, Toombs JE, Chimalapati S, Kim MS, Malladi VS, Brekken R, Orth K. Human pancreatic cancer cell exosomes, but not human normal cell exosomes, act as an initiator in cell transformation. eLife. 2019 May 73. 28;8:e40226.

  61. Masamune A, Yoshida N, Hamada S, Takikawa T, Nabeshima T, Shimosegawa T. Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells. Biochem Biophys Res Commun. 2018;495:71-77.

  62. Beloribi-Djefaflia S, Siret C, Lombardo D. Exosomal lipids induce human pancreatic tumoral MiaPaCa-2 cells resistance through the CXCR4-SDF-1 alpha signaling axis. Oncoscience. 2015;2:15-30.

  63. Beloribi S, Ristorcelli E, Breuzard G, Silvy F, Bertrand-Michel J, Beraud E, Verine A, Lombardo D. Exosomal lipids impact notch signaling and induce death of human pancreatic tumoral SOJ-6 cells. PLoS One. 2012;7:e47480.

  64. Takikawa T, Masamune A, Yoshida N, Hamada S, Kogure T, Shimosegawa T. Exosomes derived from pancreatic stellate cells: microRNA signature and effects on pancreatic cancer cells. Pancreas. 2017;46:19-27.

  65. Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, Becker A, Hoshino A, Mark MT, Molina H, Xiang J. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nature Cell Biol. 2015 Jun;17(6):816.

  66. Yu Z, Zhao S, Ren L, Wang L, Chen Z, Hoffman RM, Zhou J. Pancreatic cancer-derived exosomes promote tumor metastasis and liver pre-metastatic niche formation. Oncotarget. 2017;8:63461-83.

  67. Zhou M, Chen J, Zhou L, Chen W, Ding G, Cao L. Pancreatic cancer derived exosomes regulate the expression of TLR4 in dendritic cells via miR-203. Cell Immunol. 2014;292:65-69.

  68. Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, LeBleu VS, Mittendorf EA, Weitz J, Rahbari N, Reissfelder C. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015 Jul;523(7559):177.

  69. Lau C, Kim Y, Chia D, Spielmann N, Eibl G, Elashoff D, Wei F, Lin YL, Moro A, Grogan T, Chiang S. Role of pancreatic cancer-derived exosomes in salivary biomarker development. J Bio Chem. 2013 Sep 13;288(37):26888-97.

  70. Zhang Y, Huang S, Li P, Chen Q, Li Y, Zhou Y, Wang L, Kang M, Zhang B, Yang B, Dong X, Wu Y. Pancreatic cancer-derived exosomes suppress the production of GIP and GLP-1 from STC-lcells in vitro by down-regulating the PCSK1/3. Cancer Lett. 2018;431:190-200.

  71. Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9:581-93.

  72. Pitt JM, Charrier M, Viaud S, Andre F, Besse B, Chaput N, Zitvogel L. Dendritic cell-derived exosomes as immunotherapies in the fight against cancer. J Immunol (Baltimore, MD: 1950). 2014;193:1006-11.

  73. Xu YF, Hannafon BN, Zhao YD, Postier RG, Ding WQ. Plasma exosome miR-196a and miR-1246 are potential indicators of localized pancreatic cancer. Oncotarget. 2017;8:77028-40.

  74. Agrawal U, Sharma R, Gupta M, Vyas SP. Is nanotechnology a boon for oral drug delivery? Drug Discov Today. 2014;19:1530-46.

  75. Li C, Zhang J, Zu YJ, Nie SF, Cao J, Wang Q, Nie SP, Deng ZY, Xie MY, Wang S. Biocompatible and biodegradable nanoparticles for enhancement of anti-cancer activities of phytochemicals. Chin J Nat Med. 2015;13:641-52.

  76. Yoshida K, Burton GF, McKinney JS, Young H, Ellis EF. Brain and tissue distribution of polyethylene glycol-conjugated superoxide dismutase in rats. Stroke. 1992;23:865-69.

  77. Veronese FM, Caliceti P, Schiavon O, Sergi M. Polyethylene glycol-superoxide dismutase, a conjugate in search of exploitation. Adv Drug Delivery Rev. 2002;54:587-606.

  78. Wu H, Chen X, Ji J, Zhou R, Liu J, Ni W, Qu L, Ni H, Ni R, Bao B. Progress of exosomes in the diagnosis and treatment of pancreatic cancer. Genet Test Mol Biomark. 2019;23:215-22.

  79. Pullan JE, Confeld MI, Osborn JK, Kim J, Sarkar K, Mallik S. Exosomes as drug carriers for cancer therapy. Mol Pharm. 2019 Apr 5;16(5):1789-98.

  80. Ravindran J, Prasad S, Aggarwal BB. Curcumin and cancer cells: how many ways can curry kill tumor cells selectively? AAPS J. 2009;11:495-510.

  81. Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009;41:40-59.

  82. Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Aggarwal BB. Curcumin and cancer: an "old-age" disease with an "age-old" solution. Cancer Lett. 2008;267:133-64.

  83. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007;4:807-18.

  84. Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, Barnes S, Grizzle W, Miller D, Zhang HG. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther. 2010;18:1606-14.

  85. Ueno H, Kiyosawa K, Kaniwa N. Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy? Br J Cancer. 2007;97:145-51.

  86. Reni M, Cereda S, Galli L. PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) for patients with advanced pancreatic cancer: the ghost regimen. Cancer Lett. 2007;256:25-28.

  87. Aspe JR, Diaz Osterman CJ, Jutzy JM, Deshields S, Whang S, Wall NR. Enhancement of Gemcitabine sensitivity in pancreatic adenocarcinoma by novel exosome-mediated delivery of the Survivin-T34A mutant. J Extracell Vesicles. 2014;3.

  88. Batista IA, Melo SA. Exosomes and the future of immunotherapy in pancreatic cancer. Int J Mol Sci. 2019;20:567.

  89. Yang Y, Xiu F, Cai Z, Wang J, Wang Q, Fu Y, Cao X. Increased induction of antitumor response by exosomes derived from interleukin-2 gene-modified tumor cells. J Cancer Res Clin Oncol. 2007 Jun 1;133(6):389-99.

  90. Xie Y, Bai O, Zhang H, Li W, Xiang J. Tumor necrosis factor gene-engineered J558 tumor cell-released exosomes stimulate tumor antigen P1A-specific CD8+ CTL responses and antitumor immunity. Cancer Biother Radiopharm. 2010;25:21-28.

  91. Katsiougiannis S, Chia D, Kim Y, Singh RP, Wong DT. Saliva exosomes from pancreatic tumor-bearing mice modulate NK cell phenotype and antitumor cytotoxicity. FASEB J. 2017;31:998-1010.

  92. Morishita M, Takahashi Y, Matsumoto A, Nishikawa M, Takakura Y. Exosome-based tumor antigens-adjuvant co-delivery utilizing genetically engineered tumor cell-derived exosomes with immunostimulatory CpG DNA. Biomaterials. 2016;111:55-65.

  93. Faruqu FN, Xu L, Al-Jamal KT. Preparation of exosomes for siRNA delivery to cancer cells. J Visual Exper. 2018: e58814.

Articles with similar content:

Tissue Cross-Talk and Exosomal-MicroRNAs
Forum on Immunopathological Diseases and Therapeutics, Vol.6, 2015, issue 3-4
Micol Marchetti
Critical Aspects in Rationale Design of Fluorouracil-Based Adjuvant Therapies for the Management of Colon Cancer
Critical Reviews™ in Therapeutic Drug Carrier Systems, Vol.29, 2012, issue 2
Vivek Ranjan Sinha, Honey
Nanostructured Delivery Systems: Augmenting the Delivery of Antiretroviral Drugs for Better Management of HIV/AIDS
Critical Reviews™ in Therapeutic Drug Carrier Systems, Vol.32, 2015, issue 6
Sanaul Mustafa, Roopa S Pai, Gurinder Singh
Dendritic Cell-Derived Exosomes as Cell-Free Peptide-Based Vaccines
Critical Reviews™ in Immunology, Vol.25, 2005, issue 3
Julien Taieb, Nathalie Chaput, Laurence Zitvogel
Antiretroviral Agents: Looking for the Best Possible Chemotherapeutic Options to Conquer HIV
Critical Reviews™ in Eukaryotic Gene Expression, Vol.26, 2016, issue 4
Tahir Farooq, Muhammad Ibrahim, Muhammad Imran Qadir, Muhammad Sajid Hamid Akash, Kanwal Rehman, Arruje Hameed