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Proc Natl Acad Sci U S A. Jul 14, 2009; 106(28): 11697–11702.
Published online Jun 29, 2009. doi:  10.1073/pnas.0905930106
PMCID: PMC2710674
Medical Sciences

Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms

Abstract

A variety of mechanisms maintain the integrity of the genome in the face of cell stress. Cancer cell response to chemotherapeutic and radiation-induced DNA damage is mediated by multiple defense mechanisms including polo-like kinase 1 (Plk-1), protein kinase B (Akt-1), and/or p53 pathways leading to either apoptosis or cell cycle arrest. Subsequently, a subpopulation of arrested viable cancer cells may remain and recur despite aggressive and repetitive therapy. Here, we show that modulation (activation of Akt-1 and Plk-1 and repression of p53) of these pathways simultaneously results in paradoxical enhancement of the effectiveness of cytotoxic chemotherapy. We demonstrate that a small molecule inhibitor, LB-1.2, of protein phosphatase 2A (PP2A) activates Plk-1 and Akt-1 and decreases p53 abundance in tumor cells. Combined with temozolomide (TMZ; a DNA-methylating chemotherapeutic drug), LB-1.2 causes complete regression of glioblastoma multiforme (GBM) xenografts without recurrence in 50% of animals (up to 28 weeks) and complete inhibition of growth of neuroblastoma (NB) xenografts. Treatment with either drug alone results in only short-term inhibition/regression with all xenografts resuming rapid growth. Combined with another widely used anticancer drug, Doxorubicin (DOX, a DNA intercalating agent), LB-1.2 also causes marked GBM xenograft regression, whereas DOX alone only slows growth. Inhibition of PP2A by LB-1.2 blocks cell-cycle arrest and increases progression of cell cycle in the presence of TMZ or DOX. Pharmacologic inhibition of PP2A may be a general method for enhancing the effectiveness of cancer treatments that damage DNA or disrupt components of cell replication.

Keywords: DNA-damage responses, enhanced chemotherapy, PP2A inhibition

Multiple cellular defense pathways protect the human genome from errors in cell replication and damage from exogenous agents, including chemotherapeutic drugs and ionizing radiation used for the treatment of cancer. Regulation of mitosis by a serine/threonine kinase, Plk-1, and of apoptosis and cell cycle by Akt-1 and p53, are important for cell survival in response to DNA damage by chemotherapy and ionizing radiation (14). Because many cancers overexpress Plk-1 (57) and Akt-1 (8, 9) or have acquired p53 (4) genetic defects, inhibition of Plk-1 (1, 6, 7) and Akt-1 (8, 9) and the restoration of p53 function (4) are being widely investigated as cancer treatments. Consequently, a number of small molecules designed to improve DNA-damage response mechanisms altered in cancer cells have been synthesized and are currently in preclinical and clinical evaluation. Here we studied the opposite modulations of these DNA-damage response pathways (activation of Akt-1 and Plk-1 and repression of p53) and their effects on tumor cytotoxicity during chemotherapy. We hypothesized this modulation would inhibit the cancer defense mechanisms in response to DNA damage induced by chemotherapy agents and enhance their cytotoxic effect.

We developed a small-molecule compound, LB1.2, which specifically blocks protein phosphatase 2A (PP2A), a ubiquitous, multifunctional serine/threonine phosphatase (10). We demonstrate that LB-1.2 activates Plk-1 and Akt-1 and decreases p53 abundance in tumor cells. We investigated whether these effects would enhance the cytotoxicity in the treatment of cancers with commonly used chemotherapeutic agents. We combined LB1.2 with temozolomide (TMZ), a DNA-methylating chemotherapeutic drug, to treat glioblastoma multiforme (GBM) (11) and neuroblastoma (NB) (12) xenografts in the mouse models. We also combined LB 1.2 with Doxorubicin (DOX), a DNA intercalating chemotherapeutic drug, (13) in GBM xenografts to study whether the effect depends on the specific mechanism of the cytotoxic agent.

Our results demonstrate that accentuation rather than correction of acquired defects in the DNA-damage response of cancer cells markedly enhance the effectiveness of TMZ and DOX. We show that inhibition of PP2A accelerates malignant cell entry into S and M phase and prevents cell cycle arrest in the face of cytotoxic chemotherapy resulting in increased cell vulnerability to DNA damage, disordered replication, and death.

Results and Discussion

Previously, we demonstrated that a shellfish toxin (okadaic acid), which inhibits serine/threonine protein phosphatases PP2A and PP1, inhibits the growth and promotes differentiation of primary GBM cells (14, 15). Small molecules derived from cantharidin (a vesicant originally extracted from beetles) or its demethylated homolog (norcantharidin) mimic the effects of okadaic acid (16, 17). Modest clinical benefit of cantharidin is constrained by urologic toxicity, and norcantharidin, although less toxic, has limited effectiveness (17). We synthesized a series of norcantharidin derivatives and characterized their antiphosphatase and anticancer activity in vitro (18) and selected LB1.2 for more detailed study in vivo alone and in combination with TMZ, the standard drug for the palliative treatment of GBM.

LB-1.2 inhibits PP2A (IC50 ≈0.4 μM) with more specificity than PP1 (IC50 ≈80 μM) (Fig. 1A). Given i.p., a single dose of LB-1.2 at 1.5 mg/kg inhibits PP2A activity in s.c. xenografts of the human GBM cell line, U87MG, and in normal brain tissue (Fig. 1B). In vitro, LB-1.2 showed dose-dependant inhibition of GBM cell growth (IC50 ≈5 μM) (Fig. 1C).

Fig. 1.
Inhibition of serine/threonine phophatase activity and inhibition of proliferation of U87 cells by LB-1.2. (A) Inhibition of PP2A and PP1 activity by LB1.2. (B) PP2A activity in U87 s.c. xenografts (blue) and in normal brain tissue (red) of SCID mice ...

Exposure of U87MG cells in culture to LB-1.2 resulted in the appearance of disordered microtubules and abnormal mitotic figures that are characteristic of mitotic catastrophe, a form of cell death distinct from apoptosis and cell senescence (19, 20) (Fig. 2 A and B). Induction of mitotic catastrophe by LB-1.2 was associated with increased phosphorylated Akt-1 (pAkt-1; Fig. 2C), increased phosphorylated Plk-1 (pPlk-1), and a marked decrease in translationally controlled tumor protein (TCTP; Fig. 2D). TCTP is an abundant, highly conserved, multifunctional protein that binds to and stabilizes microtubules before and after mitosis and also exerts potent anti-apoptotic activity (2123) (Fig. 2E). Decreasing TCTP with antisense TCTP has been shown by others to enhance tumor reversion of v-src-transformed NIH 3T3 cells, and reduction of TCTP is suggested to be the mechanism by which high concentrations of certain antihistaminics and psychoactive drugs inhibit growth of a human lymphoma cell line (24).

Fig. 2.
Cellular and molecular changes in U87 cells induced by LB-1.2. (A) Nuclear changes in tumor cells in unsynchronized logarithmic growth after 24 h exposure to vehicle (control) or 2.5 μM LB-1.2 (Upper, green immunofluorescence, GFP-labeled actin ...

LB-1.2 exposure was also associated with increased phosphorylated MDM2, the primary regulator of p53 activity (3, 4), and decreased the phosphorylation of p53 (Fig. 2 F and G). The increase in MDM2 therefore diminishes a major defense against DNA damage, cell-cycle arrest by p53 (4, 25). pAkt-1 can directly phosphorylate MDM2, increasing its stability, and can also phosphorylate MDMX, which binds to and further stabilizes MDM2 (26).

pAkt-1 phosphorylation at Ser-308 indicates downstream activation of the phosphatidylinositol-3-kinase (PI3K) pathway, an event generally considered to be growth-promoting (2). Akt-1 activation, however, may be anti- or proapoptotic depending on the context of cell signaling (27). In the case of LB-1.2 inhibition of PP2A, an increase in pAkt-1 activates Plk-1, a regulator of a mitotic checkpoint and of the activity of TCTP. At the same time, increased pAkt-1 blocks cell-cycle arrest mediated by p53 in response to DNA-damage.

To determine the effect of altering DNA-damage defense mechanisms by inhibiting PP2A, we studied the effects of LB-1.2 combined with TMZ, an anticancer drug, routinely used for the palliative treatment of GBM patients (11) and combined with DOX (13). We treated severe combined immunodeficient (SCID) mice bearing s.c. xenografts of the GBM line U87MG with vehicle alone, LB-1.2 alone, TMZ alone, DOX alone, or LB-1.2 combined with either TMX or DOX, both drugs given at the same doses, and schedules as when given alone. We also studied the effect of LB-1.2 combined with TMZ on the NB line SH-SY5Y.

GBM xenografts (one in each flank of 5 mice) grew rapidly in control animals, requiring euthanizing at 3 weeks. LB-1.2 alone minimally delayed growth. TMZ alone caused complete regression for 5 weeks but with regrowth of all xenografts requiring killing of all animals by week 9. The combination of LB-1.2 and TMZ also caused complete regression of all xenografts but with delayed recurrence and regrowth in 3 animals requiring killing of 1 mouse at 13 weeks and the other 2, at 15 weeks. Two mice, however, had no recurrence in either flank after 7 months, suggesting their cancers had been eliminated (Fig. 3A). A repeat study confirmed that the 2-drug combination can cause complete regression without recurrence; in this case, 3 of 5 animals remained disease-free for >4 months (Fig. 3B). No evidence of drug toxicity was noted in either study.

Fig. 3.
Synergistic anticancer activity of LB-1.2 combined with TMZ and Dox. 5 × 106 U87MG cells in log-phase growth were inoculated s.c. into each flank of SCID mice. After the xenografts reached 0.5 ± 0.1 cm (day zero), animals were randomized ...

NB xenografts in control animals also grew rapidly, requiring killing at 3 weeks. LB-1.2 alone completely suppressed growth for 2 weeks with tumors subsequently growing more slowly than controls, not reaching a size requiring euthanizing by 7 weeks. TMZ was less inhibitory than LB-1.2. The 2-drug combination, however, completely inhibited growth, with all xenografts remaining the same size as at the start of treatment for 7 weeks (Fig. 3C).

To determine whether the potentiating effect of LB-1.2 on TMZ was unique to TMZ, we studied the effect of LB-1.2 on the therapeutic efficacy of DOX, a drug that does not methylate DNA but binds to it, interfering with the function of topoismerase type II (13). Each of 10 animals had marked regression of a single s.c. GBM xenograft, whereas treatment with either drug alone only modestly slowed tumor growth compared with animals receiving vehicle alone (Fig. 3D). The initial regimen selected was toxic, however, with 1 animal dying at 14 days, when all animals were killed. Regimens of lower doses of each drug are under study, but the results suggest that the mechanism by which LB-1.2 enhances therapeutic efficacy of a cytotoxic drug that damages DNA is independent of the mechanism by which the DNA-damage is produced.

In the drug treatment arms, some NB xenografts ulcerated by week 4, and all xenografts ulcerated by 7 weeks, requiring euthanizing per animal care protocol. None of the xenografts in control animals ulcerated, suggesting that tissue breakdown at the xenograft site is an effect of treatment. The mechanism responsible for the necrosis is not known. Histologic examination of NB xenografts 24 h after exposure to a single i.p. injection of vehicle or drug showed a homogeneous field of healthy appearing tumor cells in vehicle-treated animals, whereas LB-1.2 alone resulted in decreased cell size and pyknotic nuclei in ≈50% of cells; TMZ alone produced cytoplasmic swelling and vacuolization interspersed with a few (potentially viable) pleomorphic cells in ≈50% of cells; and LB-1.2 plus TMZ showed small pyknotic nuclei in more than 90% of cells but without the overt necrosis present after TMZ alone (Fig. 3E). Thus, the 2-drug combination prevented the growth and induced ulceration of the NB xenografts but did not cause complete regression, again without apparent toxicity.

The increase in tumor cell killing by LB-1.2 combined with TMZ or with DOX raised the possibilities that inhibition of PP2A renders cells more vulnerable and/or less efficient in repairing DNA damage because of impaired mitotic and/or DNA damage arrest. We assessed by Western blots the effects of LB-1.2, TMZ, DOX, LB-1.2 plus TMZ, and LB-1.2 plus DOX on the amount of pAkt, p53, and MDM2 in U87MG, a cell line with wild-type p53, and in U373, a cell line with mutant p53 (28). Exposure of U87MG cells to LB-1.2 alone for 24 h increased both pAkt-1 and pMDM2 and eliminated phosphorylated p53; TMZ alone and DOX alone decreased pAkt-1, increased p53, and had little effect on MDM2. Adding LB-1.2 prevented the decrease in pAkt-1 caused by TMZ alone or DOX alone and increased MDM2 in the face of continued increased expression of p53 (Fig. 4A), indicating that the effects of LB-1.2 are not specific to the type of DNA damage caused by TMZ.

Fig. 4.
Cellular and molecular changes in U87 cells exposed to LB-1.2 or okadaic acid alone and in combination with TMZ or DOX. (A) Western blots of U87 cells 24 h after exposure to LB-1.2 at 2.5 μM, TMZ at 25 μM, or DOX at 2 μM, and LB-1.2 ...

The same molecular changes in pAkt-1, p53, and MDM2 induced by LB-1.2, TMZ, and LB-1.2 plus TMZ occurred in U373 cells (Fig. 4B), indicating that the effects of PP2A inhibition are not dependent upon the presence of functional p53. Okadaic acid, at a concentration (2 nM) that is expected to inhibit PP2A and not PP1 (15), mimicked the effects of LB-1.2 on pAkt-1 and on mutant p53 in U373 cells (Fig. 4C), supporting the hypothesis that the effects of LB-1.2 result from inhibition of PP2A. The reduction of intracellular levels of p53 by exposure to LB-1.2 alone and in combination with TMZ was confirmed by immunofluorescence staining of U87 cells (Fig. 4D).

To determine the effect of PP2A inhibition on cell-cycle arrest in the face of acute DNA damage, we analyzed cell-cycle patterns of U87MG and U373 cells 48 h after exposure to TMZ, DOX alone, and in combination with LB-1.2. In U87MG cells, exposure to TMZ alone decreased the number of G1 phase cells, markedly increased S phase cells, and had little effect on G2/M phase cells. Exposure to LB-1.2 alone also decreased G1, modestly increased S, but prominently increased G2/M. Exposure to either of the 2-drug combinations resulted in patterns comparable to LB-1.2 alone, namely decreased G1 with greatly increased S and G2/M (Fig. 5A). Compared with U87MG cells, control U373 cells had slightly greater G1 and smaller G2/M compartments and a comparable S component. LB-1.2 alone had no effect on this profile. Exposure to TMZ or DOX alone reduced G1 and G2/M and greatly increased S. Exposure to either of the 2-drug combinations markedly decreased G1 and increased G2/M (Fig. 5B). There were some quantitative differences, but the primary effects of LB-1.2 combined with TMZ or with DOX were similar in both cells lines, indicating that the changes in cell cycle are not dependent on the specific action of the DNA-damaging agent and/or on the presence of functional p53.

Fig. 5.
Flow cytometric analysis of cell cycle distribution of U87 and U373 cells subject to LB-1.2, TMZ, or DOX, and LB-1.2 plus TMZ or DOX. (A) Flow cytometry profiles of U87 cells. Cell treatments were: DMSO only, LB1.2 only, 5 μM; TMZ only, 25 μM; ...

Inhibition of PP2A by LB-1.2 triggers a chain of alterations in cancer cell signaling that accelerates inappropriate entry of cells into mitosis and, at the same time, impairs arrest of cell cycle at G1 and G2/M (Fig. 6). In the face of chemotherapy-induced DNA damage and disordered cell replication, LB-1.2 up-regulates Akt-1, which has the potential to stimulate cell growth, and, at the same time, interferes with p53-mediated cell cycle arrest by stabilizing MDM2 (27). An increase in pAkt-1 activates Plk-1, interfering with activation of a checkpoint at G2/M (5, 8) and activating TCTP by phosphorylation (21). Phosphorylation of TCTP decreases the stabilization of microtubules (22, 23), which may contribute to the development of mitotic catastrophe after exposure of cancer cells to LB-1.2. We also found, however, that in the cancer cell lines and xenografts studied, pPlk-1 phosphorylation of TCTP results in a marked reduction in TCTP abundance. Loss of TCTP expression during embryogenesis increases cell death (29), presumably by reduction of TCTP anti-apoptotic activity that is mediated by interference with Bax dimerization in the mitochondrial membrane (23). Loss of TCTP induced by inhibition of PP2A may enhance cancer cell killing by the same mechanism.

Fig. 6.
Schematic illustration of the proposed mechanisms by which PP2A inhibition by LB1.2 enhances the effect of cancer chemotherapy.

Our results indicate that inhibition of PP2A increases the anticancer activity of two clinically used chemotherapeutic drugs. The combination of LB-1.2 and TMZ caused complete regression without recurrence in up to 50% of animals implanted with GBM xenografts and completely suppressed the growth of NB xenografts. If toxicity is not limiting in humans, inhibition of PP2A in cancers may be a general method for improving the effectiveness of anticancer regimens that target DNA and/or components of the mitotic process.

Materials and Methods

GBM and NB Cell Culture and Treatment.

The U87, U373, and SH-SY5Y human malignant glioma and neuroblastoma cell line were purchased from American Type Culture Collection. The U87 and U373 cell line were maintained in Eagle's minimum essential medium supplemented with 10% heat-inactivated FBS, penicillin, and streptomycin. SH-SY5Y cell was cultured in F12 medium plus L-glutamine (Gibco) containing 10% heat-inactivated FBS. Cells were seeded in triplicate in 24-well plates at a density of 2.5 × 104 cells/well. Cells were allowed to attach for at least 4 h, and the media was replaced with new media containing equal volumes of the appropriate concentrations of LB1.2 or PBS vehicle. LB1.2 was provided by Lixte Biotechnology Holdings (LBHI) under a Cooperative Research and Development Agreement between the National Institute of Neurologic Disorders and Stroke (NINDS), National Institutes of Health (NIH), and LBHI.

PP2A and PP1 Activity Assay.

Cultured tumor cells were plated in 175-cm3 flasks. When the cells were 80% confluent, the media was replaced with media containing different concentrations of LB1.2 or an equivalent volume of vehicle. After 1 h, the cells were washed 3 times in a 0.9% normal saline solution. Tissue protein extraction reagent (T-PER) (Pierce Biotechnology) solution was added to the cells, and cells were prepared for protein extraction. Lysates from each treatment group containing 300-μg protein were assayed by using a Malachite Green Phosphatase assay specific for serine/threonine phosphatase activity (Ser/Thr phosphatase assay kit 1; Millipore). PP2A activity in U87 s.c. xenografts and in normal brain tissue of SCID mice were assayed in the same conditions as above.

Proliferation Assay.

At 3 and 7 days after the start of the drug exposure, cells were counted by using a Coulter particle counter. Cells were washed with PBS, and 1 mL 0.25% trypsin was added to each well. Following cell detachment from the surface of the wells, the cells were added to 14 mL Isoton eluant. The samples were then placed in a particle counter, and cells from each well were counted 3 times.

Antibodies.

These primary antibodies were used in the study: anti-Akt, p-Akt (Thr-308), p53 (ser-15), and MDM2 (ser-166) purchased from Cell Signaling Technology; anti-TCTP, Plk1, and Plk1 (T210) purchased from Abcam. To determine the effects of LB1.2 on Akt, Plk1, TCTP, p53, and MDM2, cultured U87 cells were treated with vehicle control, 2.5 μM LB1.2. After 24 h of treatment, cultured cells were harvested and resuspended in T-PER solution, sonicated, and centrifuged. The protein concentration in each sample was measured by a colorimetric assay (Protein Assay kit; Bio-Rad Laboratories). Expression of proteins was determined via Western blotting by using primary antibodies. Detection of protein-bound primary antibodies was performed with a horseradish peroxidase-conjugated secondary antibody specific to rabbit Ig and an enhanced chemiluminescence system.

In Vivo Studies.

SCID mice at 6–8 weeks of age were purchased from Taconic. Each mouse weighed ≈20 g. Animals were housed under barrier conditions and maintained on a 12-h light/12-h dark cycle with adequate food and water supplies. After being observed for 7 days, mice were injected s.c. in both flanks with 5 × 106 U87 or SH-5YSY tumor cells suspended in PBS.

After the xenografts reached 0.5 ± 0.1 cm (day zero), animals were randomized to 4 groups of 5 animals each. Animals were treated i.p. with vehicle alone day 1–12 (50% DMSO/H2O); LB-1.2 alone at 1.5 mg/M2 on days 1–3, 5–7, and 9–11; TMZ alone at 80 mg/M2 on days 4, 8, 12; or both drugs at the same doses and schedules as when used alone. If xenografts reached a volume of 1,800 mm3, animals were killed. Tumors were measured weekly by using calipers. Tumor volumes were calculated from 2-dimensional measurements by using the following formula: tumor volume = length × width2 × π/6. All animal experiments were approved for use and care of animals under the guidelines of NIH animal protocol.

Immunofluorescence Studies.

Cultured tumors cells or xenograft tumors tissues were harvested. Touch prep slides and frozen tumor sections were prepared for immunofluorescence (IF) analysis. Following cell fixation, cells were incubated with the appropriate primary antibodies in a solution of PBS with 1% BSA and 0.1% Triton X-100 at 4 °C overnight. The primary antibodies used included: anti-phospho-Akt antibody (Thr-308), anti-p53 (ser-15), and anti-MDM2 (ser-166) (Cell Signaling Technology), anti-Plk1 (T210) (Abcam). To visualize phospho-protein staining, cells were treated with Alexa Fluor 555-conjugated goat anti-rabbit Ig (1:200 dilution; Invitrogen), or cells were treated with Alexa Fluor 488-conjugated rabbit anti-goat Ig (1:200 dilution; Invitrogen). Nuclei of cells were counterstained with 4′, 6-diamidino-2-phenylindole dihydrochloride (DAPI; Sigma-Aldrich).

Flow Cytometric Analysis of Cell Cycle.

U87 or U373 cultured cells were treated with vehicle or test regimen for 48 h. Following culture, cells were fixed with 70% ethanol overnight at −20 °C. The fixed cells were stained with 10 μg/mL PI and 1 μg/mL RNase for 30 min and analyzed by FACS (30).

Acknowledgments.

This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health and a cooperative research and development agreement between the National Institute of Neurological Disorders and Stroke at the National Institutes of Health and Lixte Biotechnology Holdings, Inc.

Footnotes

Conflict of interest statement: The authors declare a conflict of interest (such as defined by PNAS policy). J.S.K. is the founder of Lixte Biotechnology Holdings, Inc. (Lixte) and owns stock. F.J. is a consultant to Lixte and owns stock.

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