Limits...
Human Exportin-1 is a Target for Combined Therapy of HIV and AIDS Related Lymphoma.

Boons E, Vanstreels E, Jacquemyn M, Nogueira TC, Neggers JE, Vercruysse T, van den Oord J, Tamir S, Shacham S, Landesman Y, Snoeck R, Pannecouque C, Andrei G, Daelemans D - EBioMedicine (2015)

Bottom Line: Here we report on the dual anti-HIV and anti-PEL effect of targeting a single process common in both diseases.At the same time, SINE caused the nuclear accumulation of p53 tumor suppressor protein as well as inhibition of NF-κB activity in PEL cells resulting in cell cycle arrest and effective apoptosis induction.Our findings provide strong rationale for inhibiting XPO1 as an innovative strategy for the combined anti-retroviral and anti-neoplastic treatment of HIV and PEL and offer perspectives for the treatment of other AIDS-associated cancers and potentially other virus-related malignancies.

View Article: PubMed Central - PubMed

Affiliation: KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium.

ABSTRACT
Infection with HIV ultimately leads to advanced immunodeficiency resulting in an increased incidence of cancer. For example primary effusion lymphoma (PEL) is an aggressive non-Hodgkin lymphoma with very poor prognosis that typically affects HIV infected individuals in advanced stages of immunodeficiency. Here we report on the dual anti-HIV and anti-PEL effect of targeting a single process common in both diseases. Inhibition of the exportin-1 (XPO1) mediated nuclear transport by clinical stage orally bioavailable small molecule inhibitors (SINE) prevented the nuclear export of the late intron-containing HIV RNA species and consequently potently suppressed viral replication. In contrast, in CRISPR-Cas9 genome edited cells expressing mutant C528S XPO1, viral replication was unaffected upon treatment, clearly demonstrating the anti-XPO1 mechanism of action. At the same time, SINE caused the nuclear accumulation of p53 tumor suppressor protein as well as inhibition of NF-κB activity in PEL cells resulting in cell cycle arrest and effective apoptosis induction. In vivo, oral administration arrested PEL tumor growth in engrafted mice. Our findings provide strong rationale for inhibiting XPO1 as an innovative strategy for the combined anti-retroviral and anti-neoplastic treatment of HIV and PEL and offer perspectives for the treatment of other AIDS-associated cancers and potentially other virus-related malignancies.

No MeSH data available.


Related in: MedlinePlus

Anti-PEL activity of KPT-330 in vivo: growth curves of KPT-330 and vehicle control-treated BC-1 xenografts.(A) Tumor growth was determined in athymic nude mice bearing a BC-1 xenograft that received KPT-330 or vehicle treatment per os twice a week. Data were collected from two independent experiments including a total of 11 mice per group. Tumors were measured by means of a digital caliper in two directions and the formula V = (length × width2) / 2 was used to calculate the tumor volume. At week 3, animals treated with vehicle control had to be euthanized because of ethical reasons.(B) Body weight measurements of treated and vehicle control mice.(C) Tumors from placebo and KPT-330 treated mice were processed for histological examination. In both groups, tumors with a volume ≥ 1000 mm3 presented areas ≥ 25 mitosis/mm2, and < 5% p53+cells (upper panel). The smaller size tumors from KPT-330 treated mice presented only areas of 1 mitosis/mm2 and > 10% p53+ cells (lower panel).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4588406&req=5

f0030: Anti-PEL activity of KPT-330 in vivo: growth curves of KPT-330 and vehicle control-treated BC-1 xenografts.(A) Tumor growth was determined in athymic nude mice bearing a BC-1 xenograft that received KPT-330 or vehicle treatment per os twice a week. Data were collected from two independent experiments including a total of 11 mice per group. Tumors were measured by means of a digital caliper in two directions and the formula V = (length × width2) / 2 was used to calculate the tumor volume. At week 3, animals treated with vehicle control had to be euthanized because of ethical reasons.(B) Body weight measurements of treated and vehicle control mice.(C) Tumors from placebo and KPT-330 treated mice were processed for histological examination. In both groups, tumors with a volume ≥ 1000 mm3 presented areas ≥ 25 mitosis/mm2, and < 5% p53+cells (upper panel). The smaller size tumors from KPT-330 treated mice presented only areas of 1 mitosis/mm2 and > 10% p53+ cells (lower panel).

Mentions: To establish the in vivo activity to XPO1 inhibition against PEL, we engrafted athymic nude mice with BC-1 cells. Mice with tumor size of approximately 150–200 mm3 were treated with either vehicle or XPO1 inhibitor. For these in vivo studies KPT-330 (selinexor) was used. It is a chemical derivative of KPT-185 with improved PK and is the clinical candidate SINE which is currently under evaluation in multiple phase 1 and 2 studies in humans. It has been demonstrated that both KPT-330 and KPT-185 display the same drug-target interaction profile (Neggers et al., 2015). Treatment with 20 mg/kg KPT-330 only twice a week led to a significant suppression of the BC-1 PEL growth in vivo while it had no effect on body weight (Fig. 6). However, after 4 weeks of treatment in some mice tumors started to grow. Therefore, the tumors from placebo and KPT-330 treated mice were histologicaly examined at 4 weeks post-treatment (Fig. 6C). In both groups, tumors with a volume ≥ 1000 mm3 presented areas ≥ 25 mitosis/mm2 (range 26–74 mitosis/mm2) and < 5% p53+ cells. Tumors of a smaller size from KPT-330 treated mice presented only areas of 1 mitosis/mm2 and > 10% p53+ cells.


Human Exportin-1 is a Target for Combined Therapy of HIV and AIDS Related Lymphoma.

Boons E, Vanstreels E, Jacquemyn M, Nogueira TC, Neggers JE, Vercruysse T, van den Oord J, Tamir S, Shacham S, Landesman Y, Snoeck R, Pannecouque C, Andrei G, Daelemans D - EBioMedicine (2015)

Anti-PEL activity of KPT-330 in vivo: growth curves of KPT-330 and vehicle control-treated BC-1 xenografts.(A) Tumor growth was determined in athymic nude mice bearing a BC-1 xenograft that received KPT-330 or vehicle treatment per os twice a week. Data were collected from two independent experiments including a total of 11 mice per group. Tumors were measured by means of a digital caliper in two directions and the formula V = (length × width2) / 2 was used to calculate the tumor volume. At week 3, animals treated with vehicle control had to be euthanized because of ethical reasons.(B) Body weight measurements of treated and vehicle control mice.(C) Tumors from placebo and KPT-330 treated mice were processed for histological examination. In both groups, tumors with a volume ≥ 1000 mm3 presented areas ≥ 25 mitosis/mm2, and < 5% p53+cells (upper panel). The smaller size tumors from KPT-330 treated mice presented only areas of 1 mitosis/mm2 and > 10% p53+ cells (lower panel).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588406&req=5

f0030: Anti-PEL activity of KPT-330 in vivo: growth curves of KPT-330 and vehicle control-treated BC-1 xenografts.(A) Tumor growth was determined in athymic nude mice bearing a BC-1 xenograft that received KPT-330 or vehicle treatment per os twice a week. Data were collected from two independent experiments including a total of 11 mice per group. Tumors were measured by means of a digital caliper in two directions and the formula V = (length × width2) / 2 was used to calculate the tumor volume. At week 3, animals treated with vehicle control had to be euthanized because of ethical reasons.(B) Body weight measurements of treated and vehicle control mice.(C) Tumors from placebo and KPT-330 treated mice were processed for histological examination. In both groups, tumors with a volume ≥ 1000 mm3 presented areas ≥ 25 mitosis/mm2, and < 5% p53+cells (upper panel). The smaller size tumors from KPT-330 treated mice presented only areas of 1 mitosis/mm2 and > 10% p53+ cells (lower panel).
Mentions: To establish the in vivo activity to XPO1 inhibition against PEL, we engrafted athymic nude mice with BC-1 cells. Mice with tumor size of approximately 150–200 mm3 were treated with either vehicle or XPO1 inhibitor. For these in vivo studies KPT-330 (selinexor) was used. It is a chemical derivative of KPT-185 with improved PK and is the clinical candidate SINE which is currently under evaluation in multiple phase 1 and 2 studies in humans. It has been demonstrated that both KPT-330 and KPT-185 display the same drug-target interaction profile (Neggers et al., 2015). Treatment with 20 mg/kg KPT-330 only twice a week led to a significant suppression of the BC-1 PEL growth in vivo while it had no effect on body weight (Fig. 6). However, after 4 weeks of treatment in some mice tumors started to grow. Therefore, the tumors from placebo and KPT-330 treated mice were histologicaly examined at 4 weeks post-treatment (Fig. 6C). In both groups, tumors with a volume ≥ 1000 mm3 presented areas ≥ 25 mitosis/mm2 (range 26–74 mitosis/mm2) and < 5% p53+ cells. Tumors of a smaller size from KPT-330 treated mice presented only areas of 1 mitosis/mm2 and > 10% p53+ cells.

Bottom Line: Here we report on the dual anti-HIV and anti-PEL effect of targeting a single process common in both diseases.At the same time, SINE caused the nuclear accumulation of p53 tumor suppressor protein as well as inhibition of NF-κB activity in PEL cells resulting in cell cycle arrest and effective apoptosis induction.Our findings provide strong rationale for inhibiting XPO1 as an innovative strategy for the combined anti-retroviral and anti-neoplastic treatment of HIV and PEL and offer perspectives for the treatment of other AIDS-associated cancers and potentially other virus-related malignancies.

View Article: PubMed Central - PubMed

Affiliation: KU Leuven, Department of Microbiology and Immunology, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium.

ABSTRACT
Infection with HIV ultimately leads to advanced immunodeficiency resulting in an increased incidence of cancer. For example primary effusion lymphoma (PEL) is an aggressive non-Hodgkin lymphoma with very poor prognosis that typically affects HIV infected individuals in advanced stages of immunodeficiency. Here we report on the dual anti-HIV and anti-PEL effect of targeting a single process common in both diseases. Inhibition of the exportin-1 (XPO1) mediated nuclear transport by clinical stage orally bioavailable small molecule inhibitors (SINE) prevented the nuclear export of the late intron-containing HIV RNA species and consequently potently suppressed viral replication. In contrast, in CRISPR-Cas9 genome edited cells expressing mutant C528S XPO1, viral replication was unaffected upon treatment, clearly demonstrating the anti-XPO1 mechanism of action. At the same time, SINE caused the nuclear accumulation of p53 tumor suppressor protein as well as inhibition of NF-κB activity in PEL cells resulting in cell cycle arrest and effective apoptosis induction. In vivo, oral administration arrested PEL tumor growth in engrafted mice. Our findings provide strong rationale for inhibiting XPO1 as an innovative strategy for the combined anti-retroviral and anti-neoplastic treatment of HIV and PEL and offer perspectives for the treatment of other AIDS-associated cancers and potentially other virus-related malignancies.

No MeSH data available.


Related in: MedlinePlus