Unexpected chronic lymphocytic leukemia B cell activation by bisphosphonates.
Bisphosphonates
CLL cell activation
CLL cell treatment
Chronic lymphocytic leukemia (CLL)
Journal
Cancer immunology, immunotherapy : CII
ISSN: 1432-0851
Titre abrégé: Cancer Immunol Immunother
Pays: Germany
ID NLM: 8605732
Informations de publication
Date de publication:
27 Jan 2024
27 Jan 2024
Historique:
received:
01
08
2023
accepted:
25
11
2023
medline:
28
1
2024
pubmed:
28
1
2024
entrez:
27
1
2024
Statut:
epublish
Résumé
Chronic lymphocytic leukemia (CLL) is a disease of the elderly, often presenting comorbidities like osteoporosis and requiring, in a relevant proportion of cases, treatment with bisphosphonates (BPs). This class of drugs was shown in preclinical investigations to also possess anticancer properties. We started an in vitro study of the effects of BPs on CLL B cells activated by microenvironment-mimicking stimuli and observed that, depending on drug concentration, hormetic effects were induced on the leukemic cells. Higher doses induced cytotoxicity whereas at lower concentrations, more likely occurring in vivo, the drugs generated a protective effect from spontaneous and chemotherapy-induced apoptosis, and augmented CLL B cell activation/proliferation. This CLL-activation effect promoted by the BPs was associated with markers of poor CLL prognosis and required the presence of bystander stromal cells. Functional experiments suggested that this phenomenon involves the release of soluble factors and is increased by cellular contact between stroma and CLL B cells. Since CLL patients often present comorbidities such as osteoporosis and considering the diverse outcomes in both CLL disease progression and CLL response to treatment among patients, illustrating this phenomenon holds potential significance in driving additional investigations.
Identifiants
pubmed: 38280019
doi: 10.1007/s00262-023-03588-z
pii: 10.1007/s00262-023-03588-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
27Subventions
Organisme : European Union Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant
ID : 101023721
Organisme : Italian Ministry of Health RF-2021-12374376 project
ID : RF-2021-12374376
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : I.G. ID.15426
Informations de copyright
© 2024. The Author(s).
Références
Kwok M, Wu CJ (2021) Clonal evolution of high-risk chronic lymphocytic leukemia: a contemporary perspective. Front Oncol 11:790004. https://doi.org/10.3389/fonc.2021.790004
doi: 10.3389/fonc.2021.790004
pubmed: 34976831
pmcid: 8716560
Strati P, Shanafelt TD (2015) Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification. Blood 126:454–462. https://doi.org/10.1182/blood-2015-02-585059
doi: 10.1182/blood-2015-02-585059
pubmed: 26065657
pmcid: 4624440
Yang S, Varghese AM, Sood N, Chiattone C, Akinola NO, Huang X, Gale RP (2021) Ethnic and geographic diversity of chronic lymphocytic leukaemia. Leukemia 35:433–439. https://doi.org/10.1038/s41375-020-01057-5
doi: 10.1038/s41375-020-01057-5
pubmed: 33077870
Stauder R, Eichhorst B, Hamaker ME et al (2017) Management of chronic lymphocytic leukemia (CLL) in the elderly: a position paper from an international Society of Geriatric Oncology (SIOG) Task Force. Ann Oncol 28:218–227. https://doi.org/10.1093/annonc/mdw547
doi: 10.1093/annonc/mdw547
pubmed: 27803007
Gordon MJ, Kaempf A, Sitlinger A et al (2021) The chronic lymphocytic leukemia comorbidity index (CLL-CI): a three-factor comorbidity model. Clin Cancer Res 27:4814–4824. https://doi.org/10.1158/1078-0432.CCR-20-3993
doi: 10.1158/1078-0432.CCR-20-3993
pubmed: 34168050
pmcid: 8416936
Marini C, Bruno S, Fiz F et al (2017) Functional activation of osteoclast commitment in chronic lymphocytic leukaemia: a possible role for RANK/RANKL pathway. Sci Rep 7:14159. https://doi.org/10.1038/s41598-017-12761-1
doi: 10.1038/s41598-017-12761-1
pubmed: 29074954
pmcid: 5658396
Olszewski AJ, Gutman R, Eaton CB (2016) Increased risk of axial fractures in patients with untreated chronic lymphocytic leukemia: a population-based analysis. Haematologica 101:e488–e491. https://doi.org/10.3324/haematol.2016.148858
doi: 10.3324/haematol.2016.148858
pubmed: 27662013
pmcid: 5479616
Brander D, Oeffinger K, Greiner M, Dinan M (2020) Prevalence, screening, treatment, and complications of osteoporosis and osteopenia in Medicare patients with chronic lymphocytic leukemia (CLL). J Clin Oncol 38:e24050. https://doi.org/10.1200/JCO.2020.38.15_suppl.e24050
doi: 10.1200/JCO.2020.38.15_suppl.e24050
Petty L, Stephens D, Sharma A (2022) ODP090 fragility fractures and osteoporosis screening in patients with chronic lymphocytic leukemia. J Endocr Soc 6:A162. https://doi.org/10.1210/jendso/bvac150.333
doi: 10.1210/jendso/bvac150.333
pmcid: 9625023
Ebetino FH, Hogan AM, Sun S et al (2011) The relationship between the chemistry and biological activity of the bisphosphonates. Bone 49:20–33. https://doi.org/10.1016/j.bone.2011.03.774
doi: 10.1016/j.bone.2011.03.774
pubmed: 21497677
Frith JC, Monkkonen J, Blackburn GM, Russell RG, Rogers MJ (1997) Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5’-(beta, gamma-dichloromethylene) triphosphate, by mammalian cells in vitro. J Bone Miner Res 12:1358–1367. https://doi.org/10.1359/jbmr.1997.12.9.1358
doi: 10.1359/jbmr.1997.12.9.1358
pubmed: 9286751
Coscia M, Quaglino E, Iezzi M et al (2010) Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway. J Cell Mol Med 14:2803–2815. https://doi.org/10.1111/j.1582-4934.2009.00926.x
doi: 10.1111/j.1582-4934.2009.00926.x
pubmed: 19818098
Clezardin P (2011) Bisphosphonates’ antitumor activity: an unravelled side of a multifaceted drug class. Bone 48:71–79. https://doi.org/10.1016/j.bone.2010.07.016
doi: 10.1016/j.bone.2010.07.016
pubmed: 20655399
Hanna BS, McClanahan F, Yazdanparast H et al (2016) Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in vivo. Leukemia 30:570–579. https://doi.org/10.1038/leu.2015.305
doi: 10.1038/leu.2015.305
pubmed: 26522085
Weber M, Homm A, Muller S et al (2021) Zoledronate causes a systemic shift of macrophage polarization towards M1 in vivo. Int J Mol Sci 22:1323. https://doi.org/10.3390/ijms22031323
doi: 10.3390/ijms22031323
pubmed: 33525753
pmcid: 7865688
Castella B, Riganti C, Fiore F et al (2011) Immune modulation by zoledronic acid in human myeloma: an advantageous cross-talk between Vgamma9Vdelta2 T cells, alphabeta CD8+ T cells, regulatory T cells, and dendritic cells. J Immunol 187:1578–1590. https://doi.org/10.4049/jimmunol.1002514
doi: 10.4049/jimmunol.1002514
pubmed: 21753152
Silva KL, Vasconcellos DV, Castro ED, Vasconcelos FC, Bigni R, Maia RC (2008) Bisphosphonates induce apoptosis in CLL cells independently of MDR phenotype. Cancer Chemother Pharmacol 62:165–171. https://doi.org/10.1007/s00280-008-0710-1
doi: 10.1007/s00280-008-0710-1
pubmed: 18335218
Cremers S, Drake MT, Ebetino FH, Bilezikian JP, Russell RGG (2019) Pharmacology of bisphosphonates. Br J Clin Pharmacol 85:1052–1062. https://doi.org/10.1111/bcp.13867
doi: 10.1111/bcp.13867
pubmed: 30650219
pmcid: 6533426
Calissano C, Damle RN, Marsilio S et al (2011) Intraclonal complexity in chronic lymphocytic leukemia: fractions enriched in recently born/divided and older/quiescent cells. Mol Med 17:1374–1382. https://doi.org/10.2119/molmed.2011.00360
doi: 10.2119/molmed.2011.00360
pubmed: 21968788
pmcid: 3321822
Herndon TM, Chen SS, Saba NS et al (2017) Direct in vivo evidence for increased proliferation of CLL cells in lymph nodes compared to bone marrow and peripheral blood. Leukemia 31:1340–1347. https://doi.org/10.1038/leu.2017.11
doi: 10.1038/leu.2017.11
pubmed: 28074063
pmcid: 5462849
Mazzarello AN, Gentner-Gobel E, Duhren-von Minden M et al (2022) B cell receptor isotypes differentially associate with cell signaling, kinetics, and outcome in chronic lymphocytic leukemia. J Clin Invest. https://doi.org/10.1172/JCI149308
doi: 10.1172/JCI149308
pubmed: 34813501
pmcid: 8759784
Ponassi R, Biasotti B, Tomati V et al (2008) A novel Bim-BH3-derived Bcl-XL inhibitor: biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity. Cell Cycle 7:3211–3224. https://doi.org/10.4161/cc.7.20.6830
doi: 10.4161/cc.7.20.6830
pubmed: 18843207
Bruno S, Gorczyca W, Darzynkiewicz Z (1992) Effect of ionic strength in immunocytochemical detection of the proliferation associated nuclear antigens p120, PCNA, and the protein reacting with Ki-67 antibody. Cytometry 13:496–501. https://doi.org/10.1002/cyto.990130508
doi: 10.1002/cyto.990130508
pubmed: 1353016
Marini C, Cossu V, Carta S et al (2022) Fundamental role of pentose phosphate pathway within the endoplasmic reticulum in glutamine addiction of triple-negative breast cancer cells. Antioxidants (Basel). https://doi.org/10.3390/antiox12010043
doi: 10.3390/antiox12010043
pubmed: 36670904
Ghiotto F, Fais F, Tenca C et al (2009) Apoptosis of B-cell chronic lymphocytic leukemia cells induced by a novel BH3 peptidomimetic. Cancer Biol Ther 8:263–271. https://doi.org/10.4161/cbt.8.3.7424
doi: 10.4161/cbt.8.3.7424
pubmed: 19164937
Carta S, Penco F, Lavieri R, Martini A, Dinarello CA, Gattorno M, Rubartelli A (2015) Cell stress increases ATP release in NLRP3 inflammasome-mediated autoinflammatory diseases, resulting in cytokine imbalance. Proc Natl Acad Sci USA 112:2835–2840. https://doi.org/10.1073/pnas.1424741112
doi: 10.1073/pnas.1424741112
pubmed: 25730877
pmcid: 4352822
Schleiss C, Ilias W, Tahar O et al (2019) BCR-associated factors driving chronic lymphocytic leukemia cells proliferation ex vivo. Sci Rep 9:701. https://doi.org/10.1038/s41598-018-36853-8
doi: 10.1038/s41598-018-36853-8
pubmed: 30679590
pmcid: 6345919
Del Poeta G, Del Principe MI, Zucchetto A et al (2012) CD69 is independently prognostic in chronic lymphocytic leukemia: a comprehensive clinical and biological profiling study. Haematologica 97:279–287. https://doi.org/10.3324/haematol.2011.052829
doi: 10.3324/haematol.2011.052829
pubmed: 21993667
pmcid: 3269490
Shanafelt TD, Geyer SM, Bone ND et al (2008) CD49d expression is an independent predictor of overall survival in patients with chronic lymphocytic leukaemia: a prognostic parameter with therapeutic potential. Br J Haematol 140:537–546. https://doi.org/10.1111/j.1365-2141.2007.06965.x
doi: 10.1111/j.1365-2141.2007.06965.x
pubmed: 18275431
pmcid: 4477272
Boissard F, Tosolini M, Ligat L, Quillet-Mary A, Lopez F, Fournie JJ, Ysebaert L, Poupot M (2017) Nurse-like cells promote CLL survival through LFA-3/CD2 interactions. Oncotarget 8:52225–52236. https://doi.org/10.18632/oncotarget.13660
doi: 10.18632/oncotarget.13660
pubmed: 28881725
Sharma S, Rai KR (2019) Chronic lymphocytic leukemia (CLL) treatment: So many choices, such great options. Cancer 125:1432–1440. https://doi.org/10.1002/cncr.31931
doi: 10.1002/cncr.31931
pubmed: 30807655
Eichhorst B, Niemann CU, Kater AP et al (2023) First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med 388:1739–1754. https://doi.org/10.1056/NEJMoa2213093
doi: 10.1056/NEJMoa2213093
pubmed: 37163621
Romanello M, Bivi N, Pines A, Deganuto M, Quadrifoglio F, Moro L, Tell G (2006) Bisphosphonates activate nucleotide receptors signaling and induce the expression of Hsp90 in osteoblast-like cell lines. Bone 39:739–753. https://doi.org/10.1016/j.bone.2006.03.011
doi: 10.1016/j.bone.2006.03.011
pubmed: 16697713
Koch FP, Merkel C, Ziebart T, Smeets R, Walter C, Al-Nawas B (2012) Influence of bisphosphonates on the osteoblast RANKL and OPG gene expression in vitro. Clin Oral Investig 16:79–86. https://doi.org/10.1007/s00784-010-0477-8
doi: 10.1007/s00784-010-0477-8
pubmed: 20938793
Secchiero P, Corallini F, Barbarotto E, Melloni E, di Iasio MG, Tiribelli M, Zauli G (2006) Role of the RANKL/RANK system in the induction of interleukin-8 (IL-8) in B chronic lymphocytic leukemia (B-CLL) cells. J Cell Physiol 207:158–164. https://doi.org/10.1002/jcp.20547
doi: 10.1002/jcp.20547
pubmed: 16270354
Francia di Celle P, Mariani S, Riera L, Stacchini A, Reato G, Foa R (1996) Interleukin-8 induces the accumulation of B-cell chronic lymphocytic leukemia cells by prolonging survival in an autocrine fashion. Blood 87:4382–4389
doi: 10.1182/blood.V87.10.4382.bloodjournal87104382
pubmed: 8639799
Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T (1999) Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest 104:1363–1374. https://doi.org/10.1172/JCI6800
doi: 10.1172/JCI6800
pubmed: 10562298
pmcid: 409837
Baricordi OR, Melchiorri L, Adinolfi E, Falzoni S, Chiozzi P, Buell G, Di Virgilio F (1999) Increased proliferation rate of lymphoid cells transfected with the P2X(7) ATP receptor. J Biol Chem 274:33206–33208. https://doi.org/10.1074/jbc.274.47.33206
doi: 10.1074/jbc.274.47.33206
pubmed: 10559192
Adinolfi E, Melchiorri L, Falzoni S et al (2002) P2X7 receptor expression in evolutive and indolent forms of chronic B lymphocytic leukemia. Blood 99:706–708. https://doi.org/10.1182/blood.v99.2.706
doi: 10.1182/blood.v99.2.706
pubmed: 11781259
Serra S, Horenstein AL, Vaisitti T et al (2011) CD73-generated extracellular adenosine in chronic lymphocytic leukemia creates local conditions counteracting drug-induced cell death. Blood 118:6141–6152. https://doi.org/10.1182/blood-2011-08-374728
doi: 10.1182/blood-2011-08-374728
pubmed: 21998208
pmcid: 3342854
Coxon JP, Oades GM, Colston KW, Kirby RS (2004) Advances in the use of bisphosphonates in the prostate cancer setting. Prostate Cancer Prostatic Dis 7:99–104. https://doi.org/10.1038/sj.pcan.4500705
doi: 10.1038/sj.pcan.4500705
pubmed: 14993897
Aparicio A, Gardner A, Tu Y, Savage A, Berenson J, Lichtenstein A (1998) In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia 12:220–229. https://doi.org/10.1038/sj.leu.2400892
doi: 10.1038/sj.leu.2400892
pubmed: 9519785
Kimura S, Kuroda J, Segawa H, Sato K, Nogawa M, Yuasa T, Ottmann OG, Maekawa T (2004) Antiproliferative efficacy of the third-generation bisphosphonate, zoledronic acid, combined with other anticancer drugs in leukemic cell lines. Int J Hematol 79:37–43. https://doi.org/10.1007/BF02983531
doi: 10.1007/BF02983531
pubmed: 14979476
Tonti E, Jimenez de Oya N, Galliverti G et al (2013) Bisphosphonates target B cells to enhance humoral immune responses. Cell Rep 5:323–330. https://doi.org/10.1016/j.celrep.2013.09.004
doi: 10.1016/j.celrep.2013.09.004
pubmed: 24120862
Savio E, Gaudiano J, Robles AM et al (2001) Re-HEDP : pharmacokinetic characterization, clinical and dosimetric evaluation in osseous metastatic patients with two levels of radiopharmaceutical dose. BMC Nucl Med 1:2. https://doi.org/10.1186/1471-2385-1-2
doi: 10.1186/1471-2385-1-2
pubmed: 11734069
pmcid: 60657
Chen T, Berenson J, Vescio R et al (2002) Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J Clin Pharmacol 42:1228–1236. https://doi.org/10.1177/009127002762491316
doi: 10.1177/009127002762491316
pubmed: 12412821
Weiss HM, Pfaar U, Schweitzer A, Wiegand H, Skerjanec A, Schran H (2008) Biodistribution and plasma protein binding of zoledronic acid. Drug Metab Dispos 36:2043–2049. https://doi.org/10.1124/dmd.108.021071
doi: 10.1124/dmd.108.021071
pubmed: 18625688
Villikka K, Perttunen K, Rosnell J, Ikavalko H, Vaho H, Pylkkanen L (2002) The absolute bioavailability of clodronate from two different oral doses. Bone 31:418–421. https://doi.org/10.1016/s8756-3282(02)00841-4
doi: 10.1016/s8756-3282(02)00841-4
pubmed: 12231416
Sato M, Grasser W, Endo N, Akins R, Simmons H, Thompson DD, Golub E, Rodan GA (1991) Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest 88:2095–2105. https://doi.org/10.1172/JCI115539
doi: 10.1172/JCI115539
pubmed: 1661297
pmcid: 295810
Lin JH (1996) Bisphosphonates: a review of their pharmacokinetic properties. Bone 18:75–85. https://doi.org/10.1016/8756-3282(95)00445-9
doi: 10.1016/8756-3282(95)00445-9
pubmed: 8833200
Cremers SC, Pillai G, Papapoulos SE (2005) Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis. Clin Pharmacokinet 44:551–570. https://doi.org/10.2165/00003088-200544060-00001
doi: 10.2165/00003088-200544060-00001
pubmed: 15932344
Skerjanec A, Berenson J, Hsu C, Major P, Miller WH Jr, Ravera C, Schran H, Seaman J, Waldmeier F (2003) The pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with varying degrees of renal function. J Clin Pharmacol 43:154–162. https://doi.org/10.1177/0091270002239824
doi: 10.1177/0091270002239824
pubmed: 12616668
Schulz M, Schmoldt A, Andresen-Streichert H, Iwersen-Bergmann S (2020) Revisited: therapeutic and toxic blood concentrations of more than 1100 drugs and other xenobiotics. Crit Care 24:195. https://doi.org/10.1186/s13054-020-02915-5
doi: 10.1186/s13054-020-02915-5
pubmed: 32375836
pmcid: 7201985
Mitchell DY, Barr WH, Eusebio RA, Stevens KA, Duke FP, Russell DA, Nesbitt JD, Powell JH, Thompson GA (2001) Risedronate pharmacokinetics and intra- and inter-subject variability upon single-dose intravenous and oral administration. Pharm Res 18:166–170. https://doi.org/10.1023/a:1011024200280
doi: 10.1023/a:1011024200280
pubmed: 11405286
Cremers S et al (2002) A pharmacokinetic and pharmacodynamic model for intravenous bisphosphonate (pamidronate) in osteoporosis. Eur J Clin Pharmacol 57:883–890. https://doi.org/10.1007/s00228-001-0411-8
doi: 10.1007/s00228-001-0411-8
pubmed: 11936708
Haselager MV, Kater AP, Eldering E (2020) Proliferative signals in chronic lymphocytic leukemia; what are we missing? Front Oncol 10:592205. https://doi.org/10.3389/fonc.2020.592205
doi: 10.3389/fonc.2020.592205
pubmed: 33134182
pmcid: 7578574
Terpos E, Zamagni E, Lentzsch S et al (2021) Treatment of multiple myeloma-related bone disease: recommendations from the Bone Working Group of the International Myeloma Working Group. Lancet Oncol 22:e119–e130. https://doi.org/10.1016/S1470-2045(20)30559-3
doi: 10.1016/S1470-2045(20)30559-3
pubmed: 33545067
Lorange JP, Ramirez Garcia Luna J, Grou-Boileau F, Rosenzweig D, Weber MH, Akoury E (2023) Management of bone metastasis with zoledronic acid: a systematic review and Bayesian network meta-analysis. J Bone Oncol 39:100470. https://doi.org/10.1016/j.jbo.2023.100470
doi: 10.1016/j.jbo.2023.100470
pubmed: 36860585
pmcid: 9969300