Oxygen therapy in cancer treatment: progress & promises

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Review Paper 01/07/2018
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Oxygen therapy in cancer treatment: progress & promises


Low oxygen condition or hypoxia is a distinguishing feature of the tumor microenvironment, which is a well-recognized factor responsible for the limited efficacy of traditional modes of cancer treatments, such as- radiotherapy, chemotherapy and photodynamic therapy. However, oxygen therapy can reverse the hypoxia-mediated de-sensitization of hypoxic tumor cells towards the conventional cancer treatments. The efficacy of photodynamic, drugs or radiation routines is enhanced whenever oxygen therapy is coupled with conventional treatment regimes. Additionally, a significant reduction in tumor mass post-oxygen therapy is evident, irrespective of coupling it with the conventional therapy. Hyperbaric Oxygen therapy (HBOT) was earlier used in cancer treatments. Nevertheless, untargeted application of HBOT comes with severe side-effects. This drawback limits the tumor oxygenation strategy to the pre-clinical stage. However recent studies demonstrate a large number of strategies such as use of manganese oxide based depots for site specific oxygen delivery and breathing of excess of oxygen with reduced time etc., all have been discovered to achieve oxygenation of hypoxic tumor micro environment. This article reviews the important progresses made in the field of oxygen therapy. This study will be helpful in developing new therapeutic methods based on the application of oxygen, which can bypass hypoxia-induced resistance to traditional therapeutic regimes.


Balkwill FR, Capasso M, HagemannT. 2012.The tumor micro-environment at a glance.Journal of cell science,125, 5591-5596. http://dx.doi.org/10.1242/jcs.116392.

Michiels C, Tellier C, Feron O. 2016.Cycling hypoxia: a key feature of the tumor micro-environment. Biochimicaet Biophysica Acta (BBA) -Reviews on Cancer 1866, 76-86.

Forster JC, Harriss-Phillips WM, Douglass, MJ, Bezak E. 2017.A review of the development of tumor vasculature and its effects on the tumor micro-environment. Hypoxia, 5, 21-35. http://dx.doi.org/10.2147/HP.S133231

Gilkes D. 2017. Hypoxia alters the physical properties of the tumor micro-environment. In APS March Meeting Abstracts.

Petrova V, Annicchiarico-Petruzzelli M, Melino G, Amelio I. 2018. The hypoxic tumour micro-environment. Oncogenesis, 10. http://dx.doi.org/10.1038/s41389-017-0011-9

Vaupel P, Mayer A, HockelM. 2004. Tumor hypoxia and malignant progression. In Methods in enzymology 381,335-354.Academic Press.

 Rankin EB, Giaccia AJ. 2016.Hypoxic control of metastasis. Science352, 175-180. http://dx.doi.org/10.1126/science.aaf4405

Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ.1996. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. nature, 379, 88-91.

Coquelle A, Toledo F, Stern S, Bieth A, Debatisse M.1998. A new role for hypoxia in tumor progression: induction of fragile site triggering genomic rearrangements and formation of complex DMs and HSRs. Molecular cell 2,259-265.

Yuan J, Narayanan L, Rockwell S, Glazer PM.2000. Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pH. Cancer research, 60,4372-4376.

Rofstad EK. 2000. Micro-environment-induced cancer metastasis. International journal of radiation biology 76,589-605.

Harris AL. 2002. Hypoxia—a key regulatory factor in tumour growth. Nature Reviews Cancer, 2, 38.

Subarsky P, Hill RP.2003.The hypoxic tumour micro-environment and metastatic progression. Clinical & experimental metastasis 20, 237-250.

Bindra RS, Schaffer PJ, Meng A, Woo J, Måseide K, Roth ME, Glazer PM.2004. Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Molecular and cellular biology, 24, 8504-8518. http://dx.doi.org/10.1128/MCB.24.19.85048518.2004

Koshiji M, To KKW, Hammer S, Kumamoto K, HarrisAL, Modrich P, Huang LE.2005. HIF-1α induces genetic instability by transcriptionally downregulating MutSα expression. Molecular cell, 17,793-803.

HubbiME,&Semenza GL. 2015.Regulation of cell proliferation by hypoxia-inducible factors. American Journal of Physiology-Cell Physiology, 309, C775-C782.

Lindqvist LM, Tandoc K, Topisirovi I, Furic L. 2018.Cross-talk between protein synthesis, energy metabolism and autophagy in cancer. Current opinion in genetics & development 48, 104-111.

Ma R, He X, Wang H, Jia W, Zeng X. 2018. Hypoxic micro-environment promotes proliferation and invasion of non-small cell lung cancer A549 Cells through Wnt/à ²-catenin signaling pathway. Biomedical Research, 29.

Ackerman, D., & Simon, M. C. 2014. Hypoxia, lipids, and cancer: surviving the harsh tumor micro-environment. Trends in cell biology, 24,472-478.

Leithner K, Olschewski H. 2017. Progression of Lung Cancer: Role of Hypoxia and the Metabolic Tumor Microenvironment. In Mechanisms of Molecular Carcinogenesis–Volume 1,287-299. Springer, Cham.

McNeil B, Papandreou I, Denko NC. 2017.Hypoxic Reprograming of Tumor Metabolism, Matching Environmental Supply with Biosynthetic Demand. In Tumor Hypoxia, 147-167.

Sormendi S, Wielockx B. 2018. Hypoxia Pathway Proteins As Central Mediators of Metabolism in the Tumor Cells and Their Micro-environment. Frontiers in immunology 9.

 Vaupel P, Thews O, Hoeckel M. 2001.Treatment resistance of solid tumors. Medical oncology 18, 243-259.

Tredan O, Galmarini CM, Patel K, Tannock IF. 2007.Drug resistance and the solid tumor micro-environment. Journal of the National Cancer Institute99, 1441-1454.

Aouali N, Bosseler M, Sauvage D, Van Moer K, Berchem G, Janji B. 2017.The Critical Role of Hypoxia in Tumor-Mediated Immunosuppression. In Hypoxia and Human Diseases.InTech, 2017. http://dx.doi.org/10.5772/65383

Teicher BA. 1994. Hypoxia and drug resistance. Cancer and Metastasis Reviews, 13, 139-168.

Littlewood TJ. 2001. The impact of hemoglobin levels on treatment outcomes in patients with cancer. In Seminars in oncology, 28, 49-53.

Sullivan R, Paré GC, Frederiksen LJ, Semenza GL, Graham CH. 2008. Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Molecular cancer therapeutics, 7, 1961-1973.

Cosse, J. P., &Michiels, C. 2008.Tumour hypoxia affects the responsiveness of cancer cells to chemotherapy and promotes cancer progression. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 8, 790-797.

Fu P, Du F, Chen W, Yao M, Lv K, Liu Y. 2014.Tanshinone IIA blocks epithelial-mesenchymal transition through HIF-1α downregulation, reversing hypoxia-induced chemotherapy resistance in breast cancer cell lines. Oncology reports31, 2561-2568.

Gray LH, Conger A, Ebert M, Hornsey S,  Scott OCA. 1953. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. The British journal of radiology, 26,638-648.

Luna MC,  Gomer CJ. 1991.Isolation and initial characterization of mouse tumor cells resistant to porphyrin-mediated photodynamic therapy. Cancer research51, 4243-4249.

Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. 1997.Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. International Journal of Radiation Oncology• Biology• Physics, 38, 285-289.

Rofstad EK, Sundfør K, Lyng H, Trope CG. 2000. Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis. British journal of cancer 83, 354-359.

Ferrario A, Von Tiehl KF, Rucker N, Schwarz, MA, Gill PS, Gomer CJ. 2000. Antiangiogenic treatment enhances photodynamic therapy responsiveness in a mouse mammary carcinoma. Cancer research, 60, 4066-4069.

Koukourakis MI, Corti L, Skarlatos J, Giatromanolaki A, Krammer B, Blandamura, S, Beroukas K. 2001. Clinical and experimental evidence of Bcl-2 involvement in the response to photodynamic therapy. Anticancer research, 21, 663-668.

Bakalova R, Ohba H, Zhelev Z, Ishikawa M, BabaY. 2004. Quantum dots as photosensitizers?. Nature biotechnology22, 1360-1361.

Karimaian A, Majidinia M, Baghi HB, Yousefi, 2017. The crosstalk between Wnt/β-catenin signaling pathway with DNA damage response and oxidative stress: Implications in cancer therapy. DNA repair, 51, 14-19.

Rischin D, Peters LJ, O’Sullivan B, Giralt J, Fisher R, Yuen K, Henke M. 2008. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group. Oncology, 28, 2989-2995.

Williams KJ,Albertella MR, Fitzpatrick B, Loadman PM, Shnyder SD, Chinje EC, Stratford IJ. 2009. In vivo activation of the hypoxia-targeted cytotoxin AQ4N in human tumor xenografts. Molecular cancer therapeutics 8, 3266-3275. http://dx.doi.org/10.1158/1535-7163

Guise CP, Abbattista MR, Singleton RS, Holford SD, Connolly J, Dachs GU, Donate F. 2010. The bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-ketoreductase 1C3. Cancer research, 70, 1573-1584. http://dx.doi.org/10.1158/0008-5472.

Sun JD, Liu Q, Wang J, Ahluwalia D, Ferraro, D, Wang Y, Hart CP. 2012. Selective tumor hypoxia targeting by hypoxia-activated prodrug TH-302 inhibits tumor growth in preclinical models of cancer. Clinical cancer research18,758-770.

McKeage MJ, Jameson MB, Ramanathan RK., Rajendran J, Gu Y, Wilson WR, Tchekmedyian NS. 2012. PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours. BMC cancer, 12, 496.

Phillips RM, Hendriks HR, Peters GJ, EORTCPharmacology and Molecular Mechanism Group. 2013. EO9 (Apaziquone): from the clinic to the laboratory and back again. British journal of pharmacology, 168, 11-18.

Guise CP, Mowday AM, Ashoorzadeh A, Yuan R, Lin WH, Wu DH, Ding K. 2014. Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia. Chinese journal of cancer, 33, 80-86. http://dx.doi.org/10.5732/cjc.012.10285

Gill AL. Bell CN. 2004. Hyperbaric oxygen: its uses, mechanisms of action and outcomes. Qjm:An international journal of medicine, 97, 385-395.

Vaupel P, Mayer A. 2007.Hypoxia in cancer: significance and impact on clinical outcome. Cancer and Metastasis Reviews 26, 225-239.

Michieli P. 2009. Hypoxia, angiogenesis and cancer therapy: to breathe or not to breathe? Cell Cycle 8, 3291-3296.

Wenwu L, Xuejun S, Hengyi T, Kan L. 2013. Hyperbaric oxygen and cancer: more complex than we expected.Targeted oncology, 8, 79-81.

Yan L, Liang T, ChengO. 2015. Hyperbaric oxygen therapy in China. Medical gas research, 5, 3.

Thom SR. 2009. Oxidative stress is fundamental to hyperbaric oxygen therapy. Journal of applied physiology, 106, 988-995.

Gore A, Muralidhar M, Espey MG, Degenhardt K, Mantell LL. 2010.Hyperoxia sensing: from molecular mechanisms to significance in disease. Journal of immunotoxicology, 7, 239-254.

Chen YC, Chen SY, Ho PS, Lin CH, Cheng Y. Y, Wang JK, Sytwu HK. 2007. Apoptosis of T-leukemia and B-myeloma cancer cells induced by hyperbaric oxygen increased phosphorylation of p38 MAPK. Leukemia research 31, 805-815.

Raa A, Stansberg C, Steen VM, Bjerkvig R, Reed RK, Stuhr LE. 2007. Hyperoxia retards growth and induces apoptosis and loss of glands and blood vessels in DMBA-induced rat mammary tumors. BMC cancer, 7, 23.

Kawasoe Y, Yokouchi M, Ueno Y, Iwaya H, Yoshida H, Komiya S. 2009. Hyperbaric oxygen as a chemotherapy adjuvant in the treatment of osteosarcoma. Oncology reports, 22, 1045-1050.

Moen I, Øyan AM, Kalland KH, Tronstad KJ, Akslen LA, Chekenya M,  Stuhr LEB. 2009. Hyperoxic treatment induces mesenchymal-to-epithelial transition in a rat adenocarcinoma model. PloS one, 4, e6381.

Feldmeier J, Carl U, Hartmann K, SminiaP. 2003. Hyperbaric oxygen: does it promote growth or recurrence of malignancy?. Undersea & hyperbaric medicine, 30, 1-18.

Stuhr LE, Iversen VV, Straume O, MæhleBO,Reed RK. 2004. Hyperbaric oxygen alone or combined with 5-FU attenuates growth of DMBA-induced rat mammary tumors. Cancer letters 210, 35-40.

Granowitz EV, Tonomura N, Benson RM, Katz DM, Band V, Makari-Judson GP, Osborne BA. 2005. Hyperbaric oxygen inhibits benign and malignant human mammary epithelial cell proliferation. Anticancer research, 25, 3833-3842.

Daruwalla J, Christophi C. 2006. Hyperbaric oxygen therapy for malignancy: a review. World journal of surgery, 30, 2112-2131. http://dx.doi.org/10.1007/s00268-006-0190-6

Stuhr LEB, Raa A, Øyan AM, Kalland KH, Sakariassen PO, Petersen K, Reed RK. 2007. Hyperoxia retards growth and induces apoptosis, changes in vascular density and gene expression in transplanted gliomas in nude rats. Journal of neuro-oncology, 85, 191-202.

Zhe NG, Ro NGPENG, Wei-ho NGZ, Jua NL, PiNG, Tia NX. 2010.Effects of the combination of hyperbaric oxygen and 5-fluorouracil on proliferation and metastasis of human nasopharyngeal carcinoma CNE-2Z cells. Undersea & Hyperbaric Medicine 37,141-150.

Chong KT, Hampson NB, Bostwick DG, Vessella RL, Corman JM. 2004. Hyperbaric oxygen does not accelerate latent in vivo prostate cancer: implications for the treatment of radiation‐induced haemorrhagic cystitis. BJU international, 94, 1275-1278.

Shi Y, Lee CS, Wu J, Koch CJ, Thom SR, Maity A, Bernhard EJ. 2005. Effects of hyperbaric oxygen exposure on experimental head and neck tumor growth, oxygenation, and vasculature. Head & neck, 27, 362-369.

Heys SD, Smith IC, Ross JAS, Gilbert FJ. 2006. A pilot study with long term follow up of hyperbaric oxygen pretreatment in patients with locally advanced breast cancer undergoing neo-adjuvant chemotherapy. Undersea & Hyperbaric Medicine, 33, 33-43.

Schonmeyr BH, Wong AK, Reid VJ, Gewalli F, Mehrara BJ. 2008.The effect of hyperbaric oxygen treatment on squamous cell cancer growth and tumor hypoxia. Annals of plastic surgery, 60, 81-88. http://dx.doi.org/10.1097/SAP.0b013e31804a806a.

Tang H, Zhang ZY, Ge JP, Zhou WQ, Gao JP. 2009. Effects of hyperbaric oxygen on tumor growth in the mouse model of LNCaP prostate cancer cell line. National journal of andrology, 15, 713-716.

Thom SR. 2011. Hyperbaric oxygen–its mechanisms and efficacy. Plastic and reconstructive surgery, 127, 131S-141S. http://dx.doi.org/10.1097/PRS.0b013e3181fbe2bf

Moen I, Stuhr LE. 2012. Hyperbaric oxygen therapy and cancer—a review. Targeted oncology, 7, 233-242.

Seidel R, Carroll C, Thompson D, Diem RG, Yeboah K, Hayes AJ, Whelan HT. 2013. Risk factors for oxygen toxicity seizures in hyperbaric oxygen therapy: case reports from multiple institutions. Undersea &  Hyperbaric Medical Society, 40, 515-519.

Overgaard J. 1989. Sensitization of hypoxic tumour cells—clinical experience. International journal of radiation biology, 56, 801-811.

Leach RM, Rees PJ, Wilmshurst P. 1998. Hyperbaric oxygen therapy. British medical journal, 317, 1140-1143.

Takiguchi N, Saito N, Nunomura M, Kouda K, Oda K, Furuyama N, Nakajima N. 2001. Use of 5-FU plus hyperbaric oxygen for treating malignant tumors: evaluation of antitumor effect and measurement of 5-FU in individual organs. Cancer chemotherapy and pharmacology, 47, 11-14.

Siemann DW, Macler LM. 1986. Tumor radiosensitization through reductions in hemoglobin affinity. International Journal of Radiation Oncology• Biology• Physics, 12, 1295-1297.

Kalns J, Krock L, Piepmeier JE. 1998. The effect of hyperbaric oxygen on growth and chemosensitivity of metastatic prostate cancer. Anticancer research 18, 363-367.

Maier A, Tomaselli F, Anegg U, Rehak P,Fell B, Luznik S, Smolle-Jüttner FM. 2000. Combined photodynamic therapy and hyperbaric oxygenation in carcinoma of the esophagus and the esophago-gastric junction. European journal of cardio-thoracic surgery, 18, 649-655.

Chen Q, Huang Z, Chen H, Shapiro H, Beckers J, Hetzel FW. 2002. Improvement of tumor response by manipulation of tumor oxygenation during photodynamic therapy. Photochemistry and photobiology76, 197-203.

Petre PM, Baciewic  FA, Tigan S, Spears JR. 2003. Hyperbaric oxygen as a chemotherapy adjuvant in the treatment of metastatic lung tumors in a rat model. The Journal of thoracic and cardiovascular surgery, 125, 85-95.

Huang Z, Chen Q, Shakil A, Chen H, Beckers J, Shapiro H, Hetzel FW. 2003.Hyperoxygenation enhances the tumor cell killing of photofrin-mediated photodynamic therapy. Photochemistry and photobiology, 78, 496-502.

Rockwell S. 1985. Use of a perfluorochemical emulsion to improve oxygenation in a solid tumor. International Journal of Radiation Oncology, 11, 97-103.

Jain RK. 2014. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer cell, 26, 605-622.

Sorensen AG, Batchelor TT, Zhang WT, Chen PJ, Yeo P, Wang M, di Tomaso E. 2009. A “vascular normalization index” as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer research, 69, 5296-5300. http://dx.doi.org/10.1158/0008-5472.CAN-09-0814

Garcia-FoncillasJ, Martinez P, Lahuerta A, LlombartCussac A, Garcia Gonzalez M, Gomez RMS, Calvo EG. 2012. Dynamic contrast-enhanced MRI versus 18F-misonidazol-PET/CT to predict pathologic response in bevacizumab-based neoadjuvant therapy in breast cancer. Journal of clinical oncology,30,10512.

Batchelor TT, Gerstner ER, Emblem KE, Duda DG, Kalpathy-Cramer J, Snuderl M, Plotkin SR. 2013. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proceedings of the national academy of sciences, 110, 19059-19064.

Emblem KE, Mouridsen K, Bjornerud A, Farrar CT, Jennings D, Borra RJ, Jain RK. 2013. Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy. Nature medicine,19, 1178-1183.

Vasudev NS, Reynolds AR. 2014. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis17, 471-494.

Heist RS, Duda DG, Sahani DV, Ancukiewicz M, Fidias P, Sequist LV, Gandhi L. 2015. Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer. Proceedings of the National Academy of Sciences, 112, 1547-1552.

Jayson GC, Kerbel R, Ellis LM, Harris AL. 2016.Antiangiogenic therapy in oncology: current status and future directions. The Lancet388, 518-529.

Yuan F, Chen Y, Dellian M, Safabakhsh N, Ferrara N, Jain RK. 1996.Time-dependent vascular regression and permeability changes in established human tumorxenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proceedings of the National Academy of Sciences 93, 14765-14770.

Tsuzuki Y, Fukumura D, Oosthuyse B, Koike C, Carmeliet P, Jain RK. 2000. VEGF modulation by targeting HIF-1α→ HRE→ VEGF cascade differentially regulates vascular response and growth rate in tumors. Cancer Research 60, 6248-6252.

Kadambi A, Carreira CM, Yun CO, Padera T. P, Dolmans DE, Carmeliet P, Jain RK. 2001. Vascular endothelial growth factor (VEGF)-C differentially affects tumor vascular function and leukocyte recruitment: role of VEGF-receptor 2 and host VEGF-A. Cancer research, 61, 2404-2408.

Hansen-Algenstaedt N, Stoll BR, PaderaTP,Dolmans DE, Hicklin DJ, Fukumura D, Jain RK. 2000. Tumor oxygenation in hormone-dependent tumorsduring vascular endothelial growth factor receptor-2 blockade, hormone ablation, and chemotherapy. Cancer Research, 60, 4556-4560.

Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Costa S. 2011. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer cell, 19, 31-44.

Jain RK, Safabakhsh N, Sckell A, Chen Y, Jiang P, Benjamin L, Keshet E. 1998. Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor. Proceedings of the National Academy of Sciences, 95, 10820-10825.

Viloria-Petit A, Crombet T, Jothy S, Hicklin D, Bohlen P, Schlaeppi JM, Kerbel RS. 2001. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo:a role for altered tumor angiogenesis. Cancer research, 61, 5090-5101.

Stylianopoulos T, Mun LL, Jain RK. 2018.Reengineering the Tumor Vasculature: Improving Drug Delivery and Efficacy. Trends in cancer, 4, 258-259.

Stylianopoulos T, Munn LL, Jain RK. 2018. Reengineering the Physical Microenvironment of Tumors to Improve Drug Delivery and Efficacy: From Mathematical Modeling to Bench to Bedside. Trends in cancer, 4, 292-319.

Karger ER, Ohta A, Sitkovsky MV. 2015. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Science translational medicine7. http://dx.doi.org/10.1126/scitranslmed.aaa1260.

Lee S, Jeong H, Anguluan E, Kim JG. 2018. Biphasic Tumor Oxygenation during Respiratory Challenge may Predict Tumor Response during Chemotherapy. Current Optics and Photonics, 2, 1-6.

Lu Z, Ma J, Liu B, Dai C, Xie T, Ma X, Huang Q. 2016. Hyperbaric oxygen therapy sensitizes nimustine treatment for glioma in mice. Cancer medicine, 5, 3147-3155.

Sengupta A, Gupta S, Ingle A, Goda J. 2018. Hyperbaric Oxygen Therapy (HBO), DNA Damage and Tumor Progression – A Survival Study on a Mice Tumor Model. Journal of  Cancer Biology and  Research, 6, 1113.

Meng L, Cheng Y, Gan S, Zhang Z, Tong X, XuL, Hu Y. 2018. Facile Deposition of Manganese Dioxide to Albumin-Bound Paclitaxel Nanoparticles for Modulation of Hypoxic Tumor Micro-environment to Improve Chemo radiation Therapy. Molecular pharmaceutics, 15,447-457. http://dx.doi.org/10.1021/acs.molpharmaceut.7b00808

Yin Z, Chen D, Zou J, Shao J, Tang H, Xu H,  Dong X. 2018. Tumor Microenvironment Responsive Oxygen‐Self‐Generating Nanoplatform for Dual‐Imaging Guided Photodynamic and Photothermal Therapy. ChemistrySelect, 3, 4366-4373.

Guo X, Qu J, Zhu C, Li W, Luo L, Yang J, QiuY. 2018. Synchronous delivery of oxygen and photosensitizer for alleviation of hypoxia tumor micro-environment and dramatically enhanced photodynamic therapy. Drug delivery25, 585-599.

Luo Z, Zheng M, Zhao P, Chen Z, Siu F, Gong, P, Cai L. 2016. Self-monitoring artificial red cells with sufficient oxygen supply for enhanced photodynamic therapy. Scientific reports, 6, 23393. http://dx.doi.org/10.1038/srep23393

HuangWC, Shen MY, Chen HH, Lin SC,Chiang WH, Wu PH, Chiu HC. 2015. Monocytic delivery of therapeutic oxygen bubbles for dual-modality treatment of tumor hypoxia. Journal of Controlled Release, 220, 738-750.

Huang CC, Chia WT, Chung MF, Lin KJ, Hsiao CW, JinC, Sung HW. 2016. An implantable depot that can generate oxygen in situ for overcoming hypoxia-induced resistance to anticancer drugs in chemotherapy. Journal of the American Chemical Society, 138, 5222-5225. http://dx.doi.org/10.1021/jacs.6b01784

Bhandari P, Novikova G, Goergen C. J, Irudayaraj J. 2018. Ultrasound beam steering of oxygen nanobubbles for enhanced bladder cancer therapy. Scientific reports 8, 3112. http://dx.doi.org/10.1038/s41598-018-20363-8

Song X, Feng L, Liang C, Yang K, Liu Z. 2016. Ultrasound triggered tumor oxygenation with oxygen-shuttle nanoperfluorocarbon to overcome hypoxia-associated resistance in cancer therapies. Nano letters, 16, 6145-6153. http://dx.doi.org/10.1021/acs.nanolett.6b02365

Zannella VE, Dal Pra A, Muaddi H, McKee T. D, Stapleton S, Sykes J, Wouters BG. 2013. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clinical cancer research, 19, 6741-6750. http://dx.doi.org/10.1158/1078-0432.CCR-13-1787

Zhang P, Li H, Tan X, Chen L, Wang S. 2013. Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer epidemiology, 37, 207-218.

Ruan K, Song G, Ouyang G. 2009.Role of hypoxia in the hallmarks of human cancer. Journal of cellular biochemistry 107, 1053-1062.

Thomas SN, Liao Z, Clark D, Chen Y, Samadani R, Mao L, Yang AJ. 2013. Exosomal proteome profiling: a potential multi-marker cellular phenotyping tool to characterize hypoxia-induced radiation resistance in breast cancer. Proteomes1, 87-108.

Brown JM. 1999. The hypoxic cell: a target for selective cancer therapy—eighteenth Bruce F. Cain Memorial Award lecture. Cancer research, 59, 5863-5870.