Abstract
Adult T-cell /lymphomaleukemia (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Approximately 80% of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a life-threatening complication leading to a poor prognosis. Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1α (MIP-1α) are important factors in the pathogenesis of HHM in ATLL and the expression of PTHrP can be activated by nuclear factor κB (NF-κB). NF-κB is constitutively activated in ATLL cells and is essential for leukemogenesis including transformation of lymphocytes infected by HTLV-1. Our goal was to evaluate the effects of NF-κB disruption by a proteasomal inhibitor (PS-341) and osteoclastic inhibition by zoledronic acid (Zol) on the development of ATLL and HHM using a novel bioluminescent mouse model. We found that PS-341 decreased cell viability, increased apoptosis, and down-regulated PTHrP expression in ATLL cells in vitro. To investigate the in vivo efficacy, nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were xenografted with ATLL cells and treated with vehicle control, PS-341, Zol, or a combination of PS-341 and Zol. Bioluminescent imaging and tumor cell count showed a significant reduction in tumor burden in mice from all treatment groups. All treatments also significantly reduced the plasma calcium concentrations. Zol treatment increased trabecular bone volume and decreased osteoclast parameters. PS-341 reduced PTHrP and MIP-1α expression in tumor cells in vivo. Our results indicate that both PS-341 and Zol are effective treatments for ATLL and HHM, which are refractory to conventional therapy.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 11859-11866 |
| Number of pages | 8 |
| Journal | Cancer Research |
| Volume | 67 |
| Issue number | 24 |
| DOIs | |
| State | Published - Dec 15 2007 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
A novel bioluminescent mouse model and effective therapy for adult T-cell leukemia/lymphoma. / Shu, Sherry T.; Nadella, Murali V P; Dirksen, Wessel P.; Fernandez, Soledad A.; Thudi, Nanda K.; Werbeck, Jillian L.; Lairmore, Michael Dale; Rosol, Thomas J.
In: Cancer Research, Vol. 67, No. 24, 15.12.2007, p. 11859-11866.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A novel bioluminescent mouse model and effective therapy for adult T-cell leukemia/lymphoma
AU - Shu, Sherry T.
AU - Nadella, Murali V P
AU - Dirksen, Wessel P.
AU - Fernandez, Soledad A.
AU - Thudi, Nanda K.
AU - Werbeck, Jillian L.
AU - Lairmore, Michael Dale
AU - Rosol, Thomas J.
PY - 2007/12/15
Y1 - 2007/12/15
N2 - Adult T-cell /lymphomaleukemia (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Approximately 80% of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a life-threatening complication leading to a poor prognosis. Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1α (MIP-1α) are important factors in the pathogenesis of HHM in ATLL and the expression of PTHrP can be activated by nuclear factor κB (NF-κB). NF-κB is constitutively activated in ATLL cells and is essential for leukemogenesis including transformation of lymphocytes infected by HTLV-1. Our goal was to evaluate the effects of NF-κB disruption by a proteasomal inhibitor (PS-341) and osteoclastic inhibition by zoledronic acid (Zol) on the development of ATLL and HHM using a novel bioluminescent mouse model. We found that PS-341 decreased cell viability, increased apoptosis, and down-regulated PTHrP expression in ATLL cells in vitro. To investigate the in vivo efficacy, nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were xenografted with ATLL cells and treated with vehicle control, PS-341, Zol, or a combination of PS-341 and Zol. Bioluminescent imaging and tumor cell count showed a significant reduction in tumor burden in mice from all treatment groups. All treatments also significantly reduced the plasma calcium concentrations. Zol treatment increased trabecular bone volume and decreased osteoclast parameters. PS-341 reduced PTHrP and MIP-1α expression in tumor cells in vivo. Our results indicate that both PS-341 and Zol are effective treatments for ATLL and HHM, which are refractory to conventional therapy.
AB - Adult T-cell /lymphomaleukemia (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Approximately 80% of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a life-threatening complication leading to a poor prognosis. Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1α (MIP-1α) are important factors in the pathogenesis of HHM in ATLL and the expression of PTHrP can be activated by nuclear factor κB (NF-κB). NF-κB is constitutively activated in ATLL cells and is essential for leukemogenesis including transformation of lymphocytes infected by HTLV-1. Our goal was to evaluate the effects of NF-κB disruption by a proteasomal inhibitor (PS-341) and osteoclastic inhibition by zoledronic acid (Zol) on the development of ATLL and HHM using a novel bioluminescent mouse model. We found that PS-341 decreased cell viability, increased apoptosis, and down-regulated PTHrP expression in ATLL cells in vitro. To investigate the in vivo efficacy, nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were xenografted with ATLL cells and treated with vehicle control, PS-341, Zol, or a combination of PS-341 and Zol. Bioluminescent imaging and tumor cell count showed a significant reduction in tumor burden in mice from all treatment groups. All treatments also significantly reduced the plasma calcium concentrations. Zol treatment increased trabecular bone volume and decreased osteoclast parameters. PS-341 reduced PTHrP and MIP-1α expression in tumor cells in vivo. Our results indicate that both PS-341 and Zol are effective treatments for ATLL and HHM, which are refractory to conventional therapy.
UR - http://www.scopus.com/inward/record.url?scp=37549003696&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=37549003696&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-07-1701
DO - 10.1158/0008-5472.CAN-07-1701
M3 - Article
C2 - 18089816
AN - SCOPUS:37549003696
VL - 67
SP - 11859
EP - 11866
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 24
ER -