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Anti-β₂-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy.

Zhang M, He J, Liu Z, Lu Y, Zheng Y, Li H, Xu J, Liu H, Qian J, Orlowski RZ, Kwak LW, Yi Q, Yang J - Oncotarget (2015)

Bottom Line: Our results showed that anti-β2M mAbs enhanced BTZ-induced apoptosis of MM cell lines and primary MM cells.Combination treatment could also induce apoptosis of BTZ-resistant MM cells, and the enhanced effect depended on the surface expression of β2M on MM cells.BTZ treatment increased, whereas combination with anti-β2M mAbs reduced, NF-κB transcription activities in MM cells, and combination treatment inhibited NF-κB p65 binding to the beclin 1 promoter.

View Article: PubMed Central - PubMed

Affiliation: Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

ABSTRACT
Our previous studies showed that anti-β2M monoclonal antibodies (mAbs) have strong and direct apoptotic effects on multiple myeloma (MM) cells, suggesting that anti-β2M mAbs might be developed as a novel therapeutic agent. In this study, we investigated the anti-MM effects of combination treatment with anti-β2M mAbs and bortezomib (BTZ). Our results showed that anti-β2M mAbs enhanced BTZ-induced apoptosis of MM cell lines and primary MM cells. Combination treatment could also induce apoptosis of BTZ-resistant MM cells, and the enhanced effect depended on the surface expression of β2M on MM cells. BTZ up-regulated the expression of autophagy proteins, whereas combination with anti-β2M mAbs inhibited autophagy. Sequence analysis of the promoter region of beclin 1 identified 3 putative NF-κB-binding sites from -615 to -789 bp. BTZ treatment increased, whereas combination with anti-β2M mAbs reduced, NF-κB transcription activities in MM cells, and combination treatment inhibited NF-κB p65 binding to the beclin 1 promoter. Furthermore, anti-β2M mAbs and BTZ combination treatment had anti-MM activities in an established MM mouse model. Thus, our studies provide new insight and support for the clinical development of an anti-β2M mAb and BTZ combination treatment to overcome BTZ drug resistance and improve MM patient survival.

No MeSH data available.


Related in: MedlinePlus

Anti-β2M mAbs enhance anti-MM effects of BTZ in vivoShown are tumor volumes (A, B) and M-protein levels (C, D) in ARP-1 or MM.1S tumor-bearing mice, respectively (n = 4), treated with mouse IgG1 or DMSO (control), BTZ, anti-β2M mAbs (Ab), or the combination of BTZ and anti-β2M mAbs (BTZ+Ab). ARP-1 or MM.1S cells were subcutaneously injected into SCID mice. At 3 to 4 weeks after MM cell injection, mice were intraperitoneally injected with BTZ (0.1 mg/kg) or subcutaneously around tumors with anti-β2M mAbs (0.6 mg/kg), singly or in combination, every 3 days for 3 weeks. Tumor volumes were measured every 3 days after treatment. The level of circulating human kappa or lambda chain in mouse serum was measured by ELISA. (E) Representative images of in situ TUNEL assay and immunohistochemistry of Ki67 and cleaved caspase 3 (c-cas 3) showing MM tumor cell apoptosis and proliferation. **P < 0.01.
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Figure 6: Anti-β2M mAbs enhance anti-MM effects of BTZ in vivoShown are tumor volumes (A, B) and M-protein levels (C, D) in ARP-1 or MM.1S tumor-bearing mice, respectively (n = 4), treated with mouse IgG1 or DMSO (control), BTZ, anti-β2M mAbs (Ab), or the combination of BTZ and anti-β2M mAbs (BTZ+Ab). ARP-1 or MM.1S cells were subcutaneously injected into SCID mice. At 3 to 4 weeks after MM cell injection, mice were intraperitoneally injected with BTZ (0.1 mg/kg) or subcutaneously around tumors with anti-β2M mAbs (0.6 mg/kg), singly or in combination, every 3 days for 3 weeks. Tumor volumes were measured every 3 days after treatment. The level of circulating human kappa or lambda chain in mouse serum was measured by ELISA. (E) Representative images of in situ TUNEL assay and immunohistochemistry of Ki67 and cleaved caspase 3 (c-cas 3) showing MM tumor cell apoptosis and proliferation. **P < 0.01.

Mentions: We examined the therapeutic effects of anti-β2M mAb and BTZ combination treatment in vivo in a xenograft MM SCID mouse model. To detect the effects of combination treatment, low and nontherapeutic doses of BTZ and anti-β2M mAbs were chosen based on our previous studies [25, 35]. Although treatment with anti-β2M mAbs or BTZ reduced tumor volume (P < 0.05, versus control mice), combination treatment was more efficacious than BTZ alone (Figure 6A and 6B; P < 0.01). Tumor burden was further assessed by measuring serum M-protein levels by ELISA (Figure 6C and 6D; P < 0.01). No change in body weight was found in treated groups (data not shown), suggesting that the combination treatment probably had no toxic effect.


Anti-β₂-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy.

Zhang M, He J, Liu Z, Lu Y, Zheng Y, Li H, Xu J, Liu H, Qian J, Orlowski RZ, Kwak LW, Yi Q, Yang J - Oncotarget (2015)

Anti-β2M mAbs enhance anti-MM effects of BTZ in vivoShown are tumor volumes (A, B) and M-protein levels (C, D) in ARP-1 or MM.1S tumor-bearing mice, respectively (n = 4), treated with mouse IgG1 or DMSO (control), BTZ, anti-β2M mAbs (Ab), or the combination of BTZ and anti-β2M mAbs (BTZ+Ab). ARP-1 or MM.1S cells were subcutaneously injected into SCID mice. At 3 to 4 weeks after MM cell injection, mice were intraperitoneally injected with BTZ (0.1 mg/kg) or subcutaneously around tumors with anti-β2M mAbs (0.6 mg/kg), singly or in combination, every 3 days for 3 weeks. Tumor volumes were measured every 3 days after treatment. The level of circulating human kappa or lambda chain in mouse serum was measured by ELISA. (E) Representative images of in situ TUNEL assay and immunohistochemistry of Ki67 and cleaved caspase 3 (c-cas 3) showing MM tumor cell apoptosis and proliferation. **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496167&req=5

Figure 6: Anti-β2M mAbs enhance anti-MM effects of BTZ in vivoShown are tumor volumes (A, B) and M-protein levels (C, D) in ARP-1 or MM.1S tumor-bearing mice, respectively (n = 4), treated with mouse IgG1 or DMSO (control), BTZ, anti-β2M mAbs (Ab), or the combination of BTZ and anti-β2M mAbs (BTZ+Ab). ARP-1 or MM.1S cells were subcutaneously injected into SCID mice. At 3 to 4 weeks after MM cell injection, mice were intraperitoneally injected with BTZ (0.1 mg/kg) or subcutaneously around tumors with anti-β2M mAbs (0.6 mg/kg), singly or in combination, every 3 days for 3 weeks. Tumor volumes were measured every 3 days after treatment. The level of circulating human kappa or lambda chain in mouse serum was measured by ELISA. (E) Representative images of in situ TUNEL assay and immunohistochemistry of Ki67 and cleaved caspase 3 (c-cas 3) showing MM tumor cell apoptosis and proliferation. **P < 0.01.
Mentions: We examined the therapeutic effects of anti-β2M mAb and BTZ combination treatment in vivo in a xenograft MM SCID mouse model. To detect the effects of combination treatment, low and nontherapeutic doses of BTZ and anti-β2M mAbs were chosen based on our previous studies [25, 35]. Although treatment with anti-β2M mAbs or BTZ reduced tumor volume (P < 0.05, versus control mice), combination treatment was more efficacious than BTZ alone (Figure 6A and 6B; P < 0.01). Tumor burden was further assessed by measuring serum M-protein levels by ELISA (Figure 6C and 6D; P < 0.01). No change in body weight was found in treated groups (data not shown), suggesting that the combination treatment probably had no toxic effect.

Bottom Line: Our results showed that anti-β2M mAbs enhanced BTZ-induced apoptosis of MM cell lines and primary MM cells.Combination treatment could also induce apoptosis of BTZ-resistant MM cells, and the enhanced effect depended on the surface expression of β2M on MM cells.BTZ treatment increased, whereas combination with anti-β2M mAbs reduced, NF-κB transcription activities in MM cells, and combination treatment inhibited NF-κB p65 binding to the beclin 1 promoter.

View Article: PubMed Central - PubMed

Affiliation: Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

ABSTRACT
Our previous studies showed that anti-β2M monoclonal antibodies (mAbs) have strong and direct apoptotic effects on multiple myeloma (MM) cells, suggesting that anti-β2M mAbs might be developed as a novel therapeutic agent. In this study, we investigated the anti-MM effects of combination treatment with anti-β2M mAbs and bortezomib (BTZ). Our results showed that anti-β2M mAbs enhanced BTZ-induced apoptosis of MM cell lines and primary MM cells. Combination treatment could also induce apoptosis of BTZ-resistant MM cells, and the enhanced effect depended on the surface expression of β2M on MM cells. BTZ up-regulated the expression of autophagy proteins, whereas combination with anti-β2M mAbs inhibited autophagy. Sequence analysis of the promoter region of beclin 1 identified 3 putative NF-κB-binding sites from -615 to -789 bp. BTZ treatment increased, whereas combination with anti-β2M mAbs reduced, NF-κB transcription activities in MM cells, and combination treatment inhibited NF-κB p65 binding to the beclin 1 promoter. Furthermore, anti-β2M mAbs and BTZ combination treatment had anti-MM activities in an established MM mouse model. Thus, our studies provide new insight and support for the clinical development of an anti-β2M mAb and BTZ combination treatment to overcome BTZ drug resistance and improve MM patient survival.

No MeSH data available.


Related in: MedlinePlus