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Dual PI3K/mTOR inhibition is required to effectively impair microenvironment survival signals in mantle cell lymphoma.

Rosich L, Montraveta A, Xargay-Torrent S, López-Guerra M, Roldán J, Aymerich M, Salaverria I, Beà S, Campo E, Pérez-Galán P, Roué G, Colomer D - Oncotarget (2014)

Bottom Line: Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage.We found NVP-BEZ235 to be more powerful than everolimus or NVP-BKM120 in PI3K/Akt/mTOR signaling inhibition, indicating that targeting the PI3K/Akt/mTOR pathway at multiple levels is likely to be a more effective strategy for the treatment of MCL than single inhibition of these kinases.NVP-BEZ235 was the only drug able to block IL4 and IL6/STAT3 signaling which compromise the therapeutic effect of chemotherapy in MCL.

View Article: PubMed Central - PubMed

Affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

ABSTRACT
Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. Antitumor activity has been observed with mTOR inhibitors. However, they have shown limited clinical efficacy in relation to drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we have performed a comparative analysis of the mTOR inhibitor everolimus, the pan-PI3K inhibitor NVP-BKM120 and the dual PI3K/mTOR inhibitor NVP-BEZ235 in primary MCL cells. We found NVP-BEZ235 to be more powerful than everolimus or NVP-BKM120 in PI3K/Akt/mTOR signaling inhibition, indicating that targeting the PI3K/Akt/mTOR pathway at multiple levels is likely to be a more effective strategy for the treatment of MCL than single inhibition of these kinases. Among the three drugs, NVP-BEZ235 induced the highest change in gene expression profile. Functional validation demonstrated that NVP-BEZ235 inhibited angiogenesis, migration and tumor invasiveness in MCL cells. NVP-BEZ235 was the only drug able to block IL4 and IL6/STAT3 signaling which compromise the therapeutic effect of chemotherapy in MCL. Our findings support the use of the dual PI3K/mTOR inhibitor NVP-BEZ235 as a promising approach to interfere with the microenvironment-related processes in MCL.

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PI3K/Akt/mTOR inhibitors effect on CXCL12-induced MCL cell migration and invasionA, Primary MCL cells were preincubated with 5 μM everolimus, 1 μM NVP-BEZ235 or 1 μM NVP-BKM120 for 1 hour before CXCL12 (200 ng/mL) addition. Polymerized actin content was determined at the indicated time points after CXCL12 addition. Results are displayed relative to the samples (n=7) before chemokine stimulation (100 %). Bars represent the mean ± SEM. B, MCL samples (n=7) were assayed for chemotaxis toward CXCL12 after 1 hour of preincubation with the drugs. Relative number of migrating cells to the untreated control without CXCL12 is represented. Bars correspond to the mean ± SEM. C, Samples (n=7) were assayed for invasion toward CXCL12 through matrigel invasion chambers. Invasion is represented as the ratio between invasive cells and input viable cells, relative to the untreated control. Bars correspond to the mean ± SEM. *, P < 0.05.
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Figure 4: PI3K/Akt/mTOR inhibitors effect on CXCL12-induced MCL cell migration and invasionA, Primary MCL cells were preincubated with 5 μM everolimus, 1 μM NVP-BEZ235 or 1 μM NVP-BKM120 for 1 hour before CXCL12 (200 ng/mL) addition. Polymerized actin content was determined at the indicated time points after CXCL12 addition. Results are displayed relative to the samples (n=7) before chemokine stimulation (100 %). Bars represent the mean ± SEM. B, MCL samples (n=7) were assayed for chemotaxis toward CXCL12 after 1 hour of preincubation with the drugs. Relative number of migrating cells to the untreated control without CXCL12 is represented. Bars correspond to the mean ± SEM. C, Samples (n=7) were assayed for invasion toward CXCL12 through matrigel invasion chambers. Invasion is represented as the ratio between invasive cells and input viable cells, relative to the untreated control. Bars correspond to the mean ± SEM. *, P < 0.05.

Mentions: To further validate GSEA results, we next explored the role of these PI3K/Akt/mTOR inhibitors in invasive and angiogenic processes in MCL. As tumor invasiveness couples with the migratory ability of cells, we first investigated the effect of these drugs on actin polymerization and cell chemotaxis in response to CXCL12. As shown in Figure 4A, CXCL12 induced a notable increase in actin polymerization that was significantly decreased only after NVP-BEZ235 incubation (*, P < 0.05). MCL cells were then assayed for chemotaxis toward CXCL12. Figure 4B shows that everolimus and NVP-BEZ235 significantly reduced the number of migrating MCL cells in the presence of the chemokine (59.80 ± 6.87 % of inhibition for everolimus, 66.87 ± 4.78 % of inhibition for NVP-BEZ235; *, P < 0.05), whereas NVP-BKM120 had no significant effect. We then examined the effect of these drugs on MCL invasive properties with matrigel-coated invasion chambers that simulate extracellular matrix. In response to CXCL12, untreated MCL cells passed through matrigel, however, NVP-BEZ235 significantly reduced CXCL12-induced invasion (*, P < 0.05) whereas NVP-BKM120 and everolimus did not (Figure 4C).


Dual PI3K/mTOR inhibition is required to effectively impair microenvironment survival signals in mantle cell lymphoma.

Rosich L, Montraveta A, Xargay-Torrent S, López-Guerra M, Roldán J, Aymerich M, Salaverria I, Beà S, Campo E, Pérez-Galán P, Roué G, Colomer D - Oncotarget (2014)

PI3K/Akt/mTOR inhibitors effect on CXCL12-induced MCL cell migration and invasionA, Primary MCL cells were preincubated with 5 μM everolimus, 1 μM NVP-BEZ235 or 1 μM NVP-BKM120 for 1 hour before CXCL12 (200 ng/mL) addition. Polymerized actin content was determined at the indicated time points after CXCL12 addition. Results are displayed relative to the samples (n=7) before chemokine stimulation (100 %). Bars represent the mean ± SEM. B, MCL samples (n=7) were assayed for chemotaxis toward CXCL12 after 1 hour of preincubation with the drugs. Relative number of migrating cells to the untreated control without CXCL12 is represented. Bars correspond to the mean ± SEM. C, Samples (n=7) were assayed for invasion toward CXCL12 through matrigel invasion chambers. Invasion is represented as the ratio between invasive cells and input viable cells, relative to the untreated control. Bars correspond to the mean ± SEM. *, P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4196163&req=5

Figure 4: PI3K/Akt/mTOR inhibitors effect on CXCL12-induced MCL cell migration and invasionA, Primary MCL cells were preincubated with 5 μM everolimus, 1 μM NVP-BEZ235 or 1 μM NVP-BKM120 for 1 hour before CXCL12 (200 ng/mL) addition. Polymerized actin content was determined at the indicated time points after CXCL12 addition. Results are displayed relative to the samples (n=7) before chemokine stimulation (100 %). Bars represent the mean ± SEM. B, MCL samples (n=7) were assayed for chemotaxis toward CXCL12 after 1 hour of preincubation with the drugs. Relative number of migrating cells to the untreated control without CXCL12 is represented. Bars correspond to the mean ± SEM. C, Samples (n=7) were assayed for invasion toward CXCL12 through matrigel invasion chambers. Invasion is represented as the ratio between invasive cells and input viable cells, relative to the untreated control. Bars correspond to the mean ± SEM. *, P < 0.05.
Mentions: To further validate GSEA results, we next explored the role of these PI3K/Akt/mTOR inhibitors in invasive and angiogenic processes in MCL. As tumor invasiveness couples with the migratory ability of cells, we first investigated the effect of these drugs on actin polymerization and cell chemotaxis in response to CXCL12. As shown in Figure 4A, CXCL12 induced a notable increase in actin polymerization that was significantly decreased only after NVP-BEZ235 incubation (*, P < 0.05). MCL cells were then assayed for chemotaxis toward CXCL12. Figure 4B shows that everolimus and NVP-BEZ235 significantly reduced the number of migrating MCL cells in the presence of the chemokine (59.80 ± 6.87 % of inhibition for everolimus, 66.87 ± 4.78 % of inhibition for NVP-BEZ235; *, P < 0.05), whereas NVP-BKM120 had no significant effect. We then examined the effect of these drugs on MCL invasive properties with matrigel-coated invasion chambers that simulate extracellular matrix. In response to CXCL12, untreated MCL cells passed through matrigel, however, NVP-BEZ235 significantly reduced CXCL12-induced invasion (*, P < 0.05) whereas NVP-BKM120 and everolimus did not (Figure 4C).

Bottom Line: Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage.We found NVP-BEZ235 to be more powerful than everolimus or NVP-BKM120 in PI3K/Akt/mTOR signaling inhibition, indicating that targeting the PI3K/Akt/mTOR pathway at multiple levels is likely to be a more effective strategy for the treatment of MCL than single inhibition of these kinases.NVP-BEZ235 was the only drug able to block IL4 and IL6/STAT3 signaling which compromise the therapeutic effect of chemotherapy in MCL.

View Article: PubMed Central - PubMed

Affiliation: Experimental Therapeutics in Lymphoid Malignancies Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

ABSTRACT
Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. Antitumor activity has been observed with mTOR inhibitors. However, they have shown limited clinical efficacy in relation to drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we have performed a comparative analysis of the mTOR inhibitor everolimus, the pan-PI3K inhibitor NVP-BKM120 and the dual PI3K/mTOR inhibitor NVP-BEZ235 in primary MCL cells. We found NVP-BEZ235 to be more powerful than everolimus or NVP-BKM120 in PI3K/Akt/mTOR signaling inhibition, indicating that targeting the PI3K/Akt/mTOR pathway at multiple levels is likely to be a more effective strategy for the treatment of MCL than single inhibition of these kinases. Among the three drugs, NVP-BEZ235 induced the highest change in gene expression profile. Functional validation demonstrated that NVP-BEZ235 inhibited angiogenesis, migration and tumor invasiveness in MCL cells. NVP-BEZ235 was the only drug able to block IL4 and IL6/STAT3 signaling which compromise the therapeutic effect of chemotherapy in MCL. Our findings support the use of the dual PI3K/mTOR inhibitor NVP-BEZ235 as a promising approach to interfere with the microenvironment-related processes in MCL.

Show MeSH
Related in: MedlinePlus