Hypoxia: Progressive Multiple Myeloma and Its Therapy Resistance
-
Ogechi Charity Obayi
,
Emmanuella Ogbonna
,
Catherine Chinonye Eleje
,
Nwabueze Enukaorah Permsec Umerah
Abstract
This study critically reviews the role of hypoxia in the progression of Multiple Myeloma (MM)and its therapy resistance. It explains the existence and role played by Hypoxia Inducible Factors (HIF) including HIF-1α and HIF-β in tumor (MM) progression. These HIF are key transcription factors of hypoxia and they aid the cellular adaptation of both normal and cancer cells to reduction in oxygen concentration. At initial stage of MM, the bone marrow environment sufficiently supports the growth and survival of the MM cells, but as the disease progresses and the plasma cells goes deeper into the bone marrow, they experience a more hypoxic condition. This then activates HIF-1 and HIF-2 which ultimately stimulates angiogenic factors. This is a description of the step by step approaches through which a review of Hypoxia: progressive multiple myeloma and its drug resistance was conducted using Google scholar and PubMed search engines to search articles published from 2000 to May 2020 using the following key words: hypoxia, progressive multiple myeloma, treatment resistance, hypoxia and multiple myeloma. This review suggests that agents capable of inhibiting the action of HIF’s, as well as those that would act specifically on the hypoxic zones will be helpful in minimizing/eliminating drug resistance and relapses in MM patients and would invariably improves the patient life expectancy.
1. Muz B, de la Puente P, Azab F, Azab AK. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl) 2015;3:83-92.
2. Smith TG, Robbins PA, Ratcliffe PJ. The human side of hypoxia-inducible factor. Br J Haematol 2008;141(3):325-34.
3. William RW, Michael PH. Targeting hypoxia in cancer therapy. Nat Rev Cancer 2011;11(6):393-410.
4. Semenza GL. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol 2000;35(2):71-103.
5. Semenza, GL. Defining the role of HIF-1 in cancer biology and therapeutics. Oncogene 2010;29(5):625-34.
6. Martin SK, Diamond P, Gronthos S, Peet DJ, Zannettino ACW. The emerging role of hypoxia, HIF-1, and HIF-2 in multiple myeloma. Leukemia 2011;25(10):1533-42.
7. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111(5):2516-20.
8. Jinsong H, Els Van V, Eline M, Elke DB, Karin V. Understanding the hypoxic niche of multiple myeloma: therapeutic implications and contributions of mouse models. Disease model and mechanisms 2015;5(6):763-771.
9. Le QT, Denko NC, Giaccia AJ. Hypoxic gene expression and metastasis. Cancer metastasis Rev 2004;23(3-4):293-310.
10. Abdi J, Chen G, Chang H. Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms. Oncotarget 2013;4(12):2186-207.
11. Ullah MF. Cancer multidrug resistance (MDR): a major impediment to effective chemotherapy. Asian Pac J Cancer Prev 2008:9(1),1-6.
12. Gottesman MM. Mechanism of cancer drug resistance. Annu Rev Med 2002;53:615-67.
13. Sonneveld P. Multidrug resistance in hematological malignancies. J Intern Med 2000;247(5):521-34.
14. Garraway LA, James PA. Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov 2012;2(3):214-26.
15. Lü S, Wang J. The resistance mechanisms of proteasome inhibitor bortezomib. Biomark Res 2013;1(1):13. doi: 10.1186/2050-7771-1-13.
16. Hugo S, Jose EG, Vanessa P, Rui B, Vasconcelos MH. Multiple myeloma: Available therapies and causes of drug resistance. Cancer (Basel) 2020;12(2):407.
17. Dimopoulos MA, Richardson PG, Moreau P, Aderson KC. Nat Rev Clin Oncol 2015;12(1):42-54.
18. Rajkumar SV, Rafael F, Jesus F, San M. Diagnosis and Staging of Multiple Myeloma and Related Disorders. In: Dimopoulos MA, Facon T, Terpos E, editors. Multiple Myeloma and Other Plasma Cell Neoplasms. Cham (Swiss): Springer International Publishing; 2018. P. 17-28.
19. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975;36(3):842-54.
20. Greipp PR, Jesus SM, Brian GM, et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. Journal of clinical oncology 2015;33(26):2863-9.
21. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised international staging system for multiple myeloma. International myeloma working group. J Clin Oncol 2015;33(26):2863–69.
22. Ria R, Reale A, De Luisi A, Ferrucci A, Moschetta M, Vacca A. Bone marrow angiogenesis and progression in multiple myeloma. Am J Blood Res 2011;1(1):76-89.
23. Paleolog E. Hypoxia: not merely a regulator of angiogenesis? Arthritis Res Ther 2004;6(2):75–7.
24. Bhaskar, Archana, Bhupendra NT. Hypoxia inducible factor-1 alpha and multiple myeloma. Int J Adv Res (Indore) 2016;4(1):706-715.
25. Pouysségur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce
tumour regression. Nature,2006;441(7092):437–43.
26. Bos R, Zhong H, Hanrahan CF, et al. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst 2001;93(4):309–14.
27. Hoffmann AC, Mori R, Vallbohmer D et al. High expression of HIF1a is a predictor of clinical outcome in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA, VEGF, and bFGF. Neoplasia 2008;10(7):674–79.
28. Birner P, Schindl M, Obermair A, Breitenecker G, Oberhuber G. Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clin Cancer Res 2001;7(6):1661–8.
29. Theodoropoulos VE, Lazaris ACh, Sofras F, et al. Hypoxia-inducible factor 1 alpha expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. Eur Urol 2004;46(2):200–8.
30. Hu J, Handisides DR, Van Valckenborgh E, et al. Targeting the MM hypoxic niche with TH-302, a hypoxia-activated prodrug. Blood 2010;116(9):1524–7.
31. Asosingh K, De Raeve H, de Ridder M, et al. Role of the hypoxic bone marrow microenvironment in 5T2MM murine myeloma tumor progression. Haematologica 2005;90(6):810–17.
32. Martin SK, Diamond P, Williams SA, et al. Hypoxia-inducible factor-2 is a novel regulator of aberrant CXCL12 expression in multiple myeloma plasma cells. Haematologica 2010;95(5):776–84.
33. Holmquist-Mengelbier L, Fredlund E, Lofstedt T, et al. Recruitment of HIF-1alpha and HIF- 2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell 2006;10(5):413–23.
34. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407(6801):249–57.
35. Giatromanolaki A, Bai M, Margaritis D, et al. Hypoxia and activated VEGF/ receptor pathway in multiple myeloma. Anticancer Res 2010;30(7):2831–6.
36. Karakashev SV, Reginato MJ. Progress toward overcoming hypoxia_induced resistance to solid tumor therapy. Cancer Manag Res 2015;7:253-64.
37. Muz B, de la Puente P, Azab F, Laderer M, Azab AK. Hypoxia promotes stem cell-like phenotype in multiple myeloma cells. Blood Cancer J 2014;4(12):e262.
38. Prahlad VR, Giovanna DT, Slavica V, Kathryn FT. TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-kb. Cell Cycle 2016;15(4),559-72.
39. Shin DH, Chun YS, Lee DS, Huang LE, Park JW. Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxia-inducible factor-1. Blood 2008;111(6):3131-6.
40. Zhang J, Sattler M, Tonon G, et al. Targeting angiogenesis via a c-Myc/hypoxia-inducible factor-1alpha-dependent pathway in multiple myeloma. Cancer Res 2009;69(12):5082-90.
41. Lu L, Payvandi F, Wu L, et al. The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions. Microvasc Res 2009;77(2):78-86.
42. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Antimyeloma activity of heat shock protein-90 inhibition. Blood 2006;107(3):1092-100.
43. Hu Y, Kirito K, Yoshida K, et al. Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan. Mol Cancer Ther 2009;8(8),2329-38.
44. Yeo EJ, Chun YS, Cho YS, et al. YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1. J Natl Cancer Inst 2003;95(7):516-25.
45. Welsh S, Williams R, Kirkpatrock L, Paine-Murrrieta G, Powis G. Antitumor activity and pharmacodynamics properties of PX-478, an inhibitor of hypoxia-inducible factor-1 alpha. Mol Cancer Ther 2004;3(3),233-44.
46. Greenberger LM, Horak ID, Filpula D, et al. A RNA antagonist of hypoxia-inducible factor-1alpha EZN-2968, inhibits tumor cell growth. Mol Cancer Ther 2008;7(11),3598-608.
47. Olenyuk BZ, Zhang GJ, Klco JM, Nickols NG, Kaelin WG Jr, Dervan PB. Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist. Proc Natl Acad Sci U S A 2004;101(48):16768-73.
48. Park EJ, Kong D, Fisher R, Cardellina J, Shoemaker RH, Melillo G. Targeting the PAS-A domain of HIF-1alpha for development of small molecule inhibitors of HIF-1. Cell Cycle 2006;5(16):1847-53.
49. Kong D, Park EJ, Stephen AG, et al. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res 2005;65(19):9047-55.
2. Smith TG, Robbins PA, Ratcliffe PJ. The human side of hypoxia-inducible factor. Br J Haematol 2008;141(3):325-34.
3. William RW, Michael PH. Targeting hypoxia in cancer therapy. Nat Rev Cancer 2011;11(6):393-410.
4. Semenza GL. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol 2000;35(2):71-103.
5. Semenza, GL. Defining the role of HIF-1 in cancer biology and therapeutics. Oncogene 2010;29(5):625-34.
6. Martin SK, Diamond P, Gronthos S, Peet DJ, Zannettino ACW. The emerging role of hypoxia, HIF-1, and HIF-2 in multiple myeloma. Leukemia 2011;25(10):1533-42.
7. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111(5):2516-20.
8. Jinsong H, Els Van V, Eline M, Elke DB, Karin V. Understanding the hypoxic niche of multiple myeloma: therapeutic implications and contributions of mouse models. Disease model and mechanisms 2015;5(6):763-771.
9. Le QT, Denko NC, Giaccia AJ. Hypoxic gene expression and metastasis. Cancer metastasis Rev 2004;23(3-4):293-310.
10. Abdi J, Chen G, Chang H. Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms. Oncotarget 2013;4(12):2186-207.
11. Ullah MF. Cancer multidrug resistance (MDR): a major impediment to effective chemotherapy. Asian Pac J Cancer Prev 2008:9(1),1-6.
12. Gottesman MM. Mechanism of cancer drug resistance. Annu Rev Med 2002;53:615-67.
13. Sonneveld P. Multidrug resistance in hematological malignancies. J Intern Med 2000;247(5):521-34.
14. Garraway LA, James PA. Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov 2012;2(3):214-26.
15. Lü S, Wang J. The resistance mechanisms of proteasome inhibitor bortezomib. Biomark Res 2013;1(1):13. doi: 10.1186/2050-7771-1-13.
16. Hugo S, Jose EG, Vanessa P, Rui B, Vasconcelos MH. Multiple myeloma: Available therapies and causes of drug resistance. Cancer (Basel) 2020;12(2):407.
17. Dimopoulos MA, Richardson PG, Moreau P, Aderson KC. Nat Rev Clin Oncol 2015;12(1):42-54.
18. Rajkumar SV, Rafael F, Jesus F, San M. Diagnosis and Staging of Multiple Myeloma and Related Disorders. In: Dimopoulos MA, Facon T, Terpos E, editors. Multiple Myeloma and Other Plasma Cell Neoplasms. Cham (Swiss): Springer International Publishing; 2018. P. 17-28.
19. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975;36(3):842-54.
20. Greipp PR, Jesus SM, Brian GM, et al. Revised international staging system for multiple myeloma: a report from International Myeloma Working Group. Journal of clinical oncology 2015;33(26):2863-9.
21. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised international staging system for multiple myeloma. International myeloma working group. J Clin Oncol 2015;33(26):2863–69.
22. Ria R, Reale A, De Luisi A, Ferrucci A, Moschetta M, Vacca A. Bone marrow angiogenesis and progression in multiple myeloma. Am J Blood Res 2011;1(1):76-89.
23. Paleolog E. Hypoxia: not merely a regulator of angiogenesis? Arthritis Res Ther 2004;6(2):75–7.
24. Bhaskar, Archana, Bhupendra NT. Hypoxia inducible factor-1 alpha and multiple myeloma. Int J Adv Res (Indore) 2016;4(1):706-715.
25. Pouysségur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce
tumour regression. Nature,2006;441(7092):437–43.
26. Bos R, Zhong H, Hanrahan CF, et al. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst 2001;93(4):309–14.
27. Hoffmann AC, Mori R, Vallbohmer D et al. High expression of HIF1a is a predictor of clinical outcome in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA, VEGF, and bFGF. Neoplasia 2008;10(7):674–79.
28. Birner P, Schindl M, Obermair A, Breitenecker G, Oberhuber G. Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clin Cancer Res 2001;7(6):1661–8.
29. Theodoropoulos VE, Lazaris ACh, Sofras F, et al. Hypoxia-inducible factor 1 alpha expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. Eur Urol 2004;46(2):200–8.
30. Hu J, Handisides DR, Van Valckenborgh E, et al. Targeting the MM hypoxic niche with TH-302, a hypoxia-activated prodrug. Blood 2010;116(9):1524–7.
31. Asosingh K, De Raeve H, de Ridder M, et al. Role of the hypoxic bone marrow microenvironment in 5T2MM murine myeloma tumor progression. Haematologica 2005;90(6):810–17.
32. Martin SK, Diamond P, Williams SA, et al. Hypoxia-inducible factor-2 is a novel regulator of aberrant CXCL12 expression in multiple myeloma plasma cells. Haematologica 2010;95(5):776–84.
33. Holmquist-Mengelbier L, Fredlund E, Lofstedt T, et al. Recruitment of HIF-1alpha and HIF- 2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell 2006;10(5):413–23.
34. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407(6801):249–57.
35. Giatromanolaki A, Bai M, Margaritis D, et al. Hypoxia and activated VEGF/ receptor pathway in multiple myeloma. Anticancer Res 2010;30(7):2831–6.
36. Karakashev SV, Reginato MJ. Progress toward overcoming hypoxia_induced resistance to solid tumor therapy. Cancer Manag Res 2015;7:253-64.
37. Muz B, de la Puente P, Azab F, Laderer M, Azab AK. Hypoxia promotes stem cell-like phenotype in multiple myeloma cells. Blood Cancer J 2014;4(12):e262.
38. Prahlad VR, Giovanna DT, Slavica V, Kathryn FT. TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-kb. Cell Cycle 2016;15(4),559-72.
39. Shin DH, Chun YS, Lee DS, Huang LE, Park JW. Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxia-inducible factor-1. Blood 2008;111(6):3131-6.
40. Zhang J, Sattler M, Tonon G, et al. Targeting angiogenesis via a c-Myc/hypoxia-inducible factor-1alpha-dependent pathway in multiple myeloma. Cancer Res 2009;69(12):5082-90.
41. Lu L, Payvandi F, Wu L, et al. The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions. Microvasc Res 2009;77(2):78-86.
42. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Antimyeloma activity of heat shock protein-90 inhibition. Blood 2006;107(3):1092-100.
43. Hu Y, Kirito K, Yoshida K, et al. Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan. Mol Cancer Ther 2009;8(8),2329-38.
44. Yeo EJ, Chun YS, Cho YS, et al. YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1. J Natl Cancer Inst 2003;95(7):516-25.
45. Welsh S, Williams R, Kirkpatrock L, Paine-Murrrieta G, Powis G. Antitumor activity and pharmacodynamics properties of PX-478, an inhibitor of hypoxia-inducible factor-1 alpha. Mol Cancer Ther 2004;3(3),233-44.
46. Greenberger LM, Horak ID, Filpula D, et al. A RNA antagonist of hypoxia-inducible factor-1alpha EZN-2968, inhibits tumor cell growth. Mol Cancer Ther 2008;7(11),3598-608.
47. Olenyuk BZ, Zhang GJ, Klco JM, Nickols NG, Kaelin WG Jr, Dervan PB. Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist. Proc Natl Acad Sci U S A 2004;101(48):16768-73.
48. Park EJ, Kong D, Fisher R, Cardellina J, Shoemaker RH, Melillo G. Targeting the PAS-A domain of HIF-1alpha for development of small molecule inhibitors of HIF-1. Cell Cycle 2006;5(16):1847-53.
49. Kong D, Park EJ, Stephen AG, et al. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res 2005;65(19):9047-55.
| Files | ||
| Issue | Vol 9, No 1 (Winter 2021) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/jpc.v9i1.6036 | |
| Keywords | ||
| Hypoxia;Multiple Myeloma;Drug Resistance, Neoplasm | ||
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How to Cite
1.
Obayi O, Ogbonna E, Eleje C, Umerah N. Hypoxia: Progressive Multiple Myeloma and Its Therapy Resistance. J Pharm Care. 2021;9(1):45-51.
