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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Curr Pharm Des. Author manuscript; available in PMC 2013 September 23.
Published in final edited form as:
PMCID: PMC3780581
NIHMSID: NIHMS501501

Pharmacological Activation of p53 in Cancer Cells

Abstract

Tumor suppressor p53 is a transcription factor that regulates a large number of genes and guards against genomic instability. Under multiple cellular stress conditions, p53 functions to block cell cycle progression transiently unless proper DNA repair occurs. Failure of DNA repair mechanisms leads to p53-mediated induction of cell death programs. p53 also induces permanent cell cycle arrest known as cellular senescence. During neoplastic progression, p53 is often mutated and fails to efficiently perform these functions. It has been observed that cancers carrying a wild-type p53 may also have interrupted downstream p53 regulatory signaling leading to disruption in p53 functions. Therefore, strategies to reactivate p53 provide an attractive approach for blocking tumor pathogenesis and its progression. p53 activation may also lead to regression of existing early neoplastic lesions and therefore may be important in developing cancer chemoprevention protocols. A large number of small molecules capable of reactivating p53 have been developed and some are progressing through clinical trials for prospective human applications. However, several questions remain to be answered at this stage. For example, it is not certain if pharmacological activation of p53 will restore all of its multifaceted biological responses, assuming that the targeted cell is not killed following p53 activation. It remains to be demonstrated whether the distinct biological effects regulated by specific post-transnationally modified p53 can effectively be restored by refolding mutant p53. Mutant p53 can be classified as a loss of function or gain of function protein depending on the type of mutation. It is also unclear whether reactivation of mutant p53 has similar consequences in cells carrying gain-of-function and loss-of-function p53 mutants. This review provides a description of various pharmacological approaches tested to activate p53 (both wild-type and mutant) and to assess the effects of activated p53 on neoplastic progression

Keywords: p53, cancer therapeutics, mutant p53 refolding, restoration of tumor suppressor functions, mdm2

I. INTRODUCTION

p53 is a major tumor suppressor discovered as a cellular SV40 large T-antigen binding protein in 1979 [1]. Since then, there has been tremendous interest in discovering its role in diverse cellular functions, particularly under stress conditions. The importance of this tumor suppressor became more evident when approximately 50% of all cancers were discovered to have mutant p53 and the remaining tumors showed disrupted downstream pathways known to be involved in the activation and homeostasis of this protein [2]. Defects in p53-dependent functions allow cancer cells to escape normal stress responses. The ability of p53 to manifest growth arrest or induce apoptosis in response to diverse cellular stresses, such as DNA damage, oncogenic activation, hypoxia, etc., are considered as key functions for its tumor suppressor activities [3]. Interestingly, recent studies highlighted its role in various other diverse cellular functions in addition to balancing cell growth and death. These special functions include but are not limited to autophagy, cellular metabolism, and extracellular effects that regulate tumor stroma, angiogenesis, metastasis, and escape from innate immune responses [4]. However, current pharmacological approaches de-signed to activate wild-type p53 or revert mutant p53 to perform wild-type functions focus primarily on cell cycle regulation, DNA repair, cellular redox state, and anti-apoptotic activities [5,6]. Table 1 summarizes the majority of the therapeutic approaches related to p53. However, this review provides a description of a sample of important small molecules which have been tested in a variety of cancer models. Finally, a recent study provided a basis for a thera-peutic approach that may selectively inhibit tumors in p53 deficient patients using small molecules [120].

Table 1
Summary of p53-based Therapeutic Approaches

II. DEVELOPMENT OF SMALL MOLECULES FOR p53 ACTIVATION

i. Activating Wild-type p53

Since 50% of tumors carry wild-type p53 which is nonfunctional as a result of disruption in downstream signaling regulating its cellular levels, this therapeutic strategy focuses on rectifying these downstream signaling regulating proteins [7]. In this regard, the emphasis is on developing small molecule inhibitors of E3 ligase activity of MDM2 or on developing agents that can bind the hydrophobic p53 pocket in MDM2 [8]. One concern that must be addressed before these molecules can be taken to the clinic is their toxicity in normal tissues. It is likely that these agents may induce p53 in normal cells, causing their non-specific toxicity. However, potential toxicity in normal cells depends on the ability of these chemicals to induce differential p53 protein concentrations between normal and cancer cells.

A. Targeting Mdm2-p53 Axis

Based on the fact that in normal cells p53 levels are kept low through the activity of its negative regulator degrading enzymes, these proteins have been considered as therapeutic targets in cancers carrying wild-type p53. The most extensively studied p53 degrading enzyme is an E3 ubiquitin ligase, MDM2 (designated as HDM2 in humans), which binds to the N-terminal transcriptional activation domain of p53. The binding of MDM2 with p53 inhibits its transcriptional act ivit y and targets it for proteosomal degradation. It is known that interruption of MDM2/p53 interactions leads to the cellular accumulation of p53 protein following various stress conditions including DNA damage. p53 accumulation may have severe consequences ranging between a reversible cell cycle arrest, induction of DNA repair machinery, senescence, or cell death [5,7,8]. The exact molecular mechanism for regulating this range of effects is not well characterized. However, several p53 partner proteins or enzymes important in its post-translational modifications can dictate the manifestations between cell cycle arrest and apoptosis [9]. Pharmacological reactivation of p53 by small molecules that target MDM2 is considered as an important approach to therapy of cancers retaining wild-type p53 gene but carrying compromised functional components due to dysregulation of MDM2.

a. RITA, (reactivation of p53 and induction of tumor cell apoptosis) is a small molecule which was identified in a cell-based screen for wild-type p53-reactivating compounds. RITA prevents p53-HDM2 interaction both in vitro and in vivo. It has also affected p53 interactions with its several negative regulators Treatment of wild-type p53 carrying tumor cells with RITA induced p53 target genes and manifested massive apoptosis [10]. RITA also suppressed the growth of human fibroblasts and lymphoblasts only upon oncogene expression and showed substantial p53-dependent antitumor effects in vivo. It has also been shown that MDM2 released from p53 by RITA promotes degradation of p21 and the p53 cofactor hnRNP K, required for the transcription of p21. These studies also uncovered that MDM2-dependent inhibition of p21 acts as a switch capable of regulating cell fate decisions upon p53 reactivation. In an independent study it was shown that RITA-mediated p53 activation [11] unleashes the transcriptional repression of anti-apoptotic proteins, Mcl-1, Bcl-2, MAP4, and survivin. In addition, it blocks the Akt signaling pathway on various levels by down regulating c-Myc, cyclin E, and j3-catenin [12]. Interestingly, these studies show that the threshold for p53-mediated repression of survival genes is higher than for transactivation of pro-apoptotic target genes [13]. Furthermore, these studies demonstrate that inhibition of oncogenes by p53 reduces the cell's ability to buffer pro-apoptotic signals leading to robust apoptosis [14].

b. Nutlins, cis-imidazoline analogs, are another category of very well studied inhibitors of MDM2-p53 complex. These agents strongly bind with and selectively inhibit MDM2. Among this class of compounds nutlin-3 is known to displace p53 from MDM2-p53 complex by blocking the MDM2 binding pocket in p53 [15]. As learned from murine models, deletion of the MDM2 gene is highly toxic. However, pharmacological antagonism does not manifest major toxicity [16]. Treatment of tumor cells with MDM2 inhibitors induces apoptosis both in vitro and in murine xenograft models. However, normal non-malignant cells and tissues remain largely unaffected [17]. In different tumor types, nutlin treatment has been shown to induce apoptosis or senescence [18]. It also inhibits autophagy and affects tumor tissue differentiation programming [19], however the mechanisms by which these changes are regulated are not clearly understood. Nutlin-3 was found to be effective against a variety of tumor-types including acute myelogeneous leukemia, myeloma, and acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia, neuroblastoma, in addition to some other solid malignancies [20]. Additional studies conducted with a combinatorial approach using nutlin-3 and other established anti-tumor agents, for example vinblastine or roscovitine, etc., showed a synergistic tumor inhibitory action [21]. In contrast to these positive effects, tumor resistance to nutlin-3 treatment has also been reported. It has been shown that nutlin-3 treatment results in a p53-dependent activation of NOTCH1 which, in turn, limits the apoptosis inducing effects of nutlin-3. Support for this notion is provided by studies in which treatment of tumor cells with nutlin-3 and y-secretase inhibitors DAPT and L-685458, the known blockers of NOTCH signaling pathway were found effective in overcoming tumor resistance against nutlin-3 [22]. In a murine model of prostate carcinogenesis, nutlin-3 was found to enhance PTEN-loss-induced cellular senescence (PICS) leading to tumor regression [23].

c. Other Approaches to Induce Wild-type p53

A number of other approaches to induce wild-type p53 have proved successful in cell culture and xenograft murine model systems. In this regard, tenovin-1 and tenovin-6 were found to reversibly increase p53 and p21CIP/WAF1 expression and decrease cellular growth. These agents were found to be potent inhibitors of SIRT1 and SIRT2. SIRT1 is an important known negative regulator of p53 functions [24]. Other agents that are included in this category are MDM4/MDMX inhibitors and nuclear export signal inhibitors [2527]. Although these agents have promise for development as important therapeutic agents, studies are required to under-stand their exact mechanisms of action, off-target effects and to define their utility as either single agents or a part of a combinatorial protocol with other p53 regulating or chemotherapeutic drugs. It is likely that these agents may be helpful in the restoration of chemical sensitivity against chemo-resistance in cancer cells.

ii. REACTIVATING MUTANT p53

The high frequency of p53 mutations in human cancers and increased resistance of mutant p53 expressing tumors to conventional chemotherapy and radiation therapy makes mutant p53 an appealing cancer therapy target [28]. Further support for this concept comes from studies demonstrating that restoration of p53 expression in p53 deficient murine tumors triggers efficient removal of tumor cells. However, mutant p53 reactivation remains a challenge since a range of p53 mutations occur in human tumors. These mutations may give rise to unique structural alterations in the p53 protein [29] and therefore a single small molecule-mediated reversion of mutant p53 to wild-type conformation may not prove very efficient.

a. Various strategies were adopted for the discovery of mutant p53 reactivating chemical compounds. In this regard, the use of reverse chemicogenetic approaches led to identification of CP-31398, an agent found to refold mutant p53 into its wild-type conformation. This restoration of wild-type epitope (the 1620 epitope) to mutant p53 protein was associated with the transcriptional activation of p53 target genes. CP-31398 manifested anti-tumor effects in murine xenograft models [30]. Interestingly, this small molecule was also found to stabilize wild-type p53 protein through its reduced ubiquitination [31]. CP-31398 was found to restore wild-type p53 functions to multiple p53 mutants although there is a lack of evidence that any stable physical association occurs between CP-31398 and mutant p53 proteins [32]. Although there is a controversy about the exact mechanism of action of this Pfizer compound [33], it is assumed that it intercalates with DNA to manifest the observed tumor growth blocking effects [34].

Recently, we demonstrated the chemopreventive and chemotherapeutic effects of CP-31398 in a SKH-1 murine skin neoplasm [35]. Similar to humans who develop epidermal hyperplasia, actinic keratoses, and SCCs, these animals manifest pathogenesis of skin hyperplasia, benign squamous papillomas, and SCCs following chronic UVB irradiation [36]. The molecular changes-associated with the pathobiology of these lesions in SKH-1 mice closely resembles that of sun-exposed human skin. These studies showed that CP-31398 restores p53-dependent cell cycle arrest and apoptosis in UVB-irradiated p53+/+ skin but not in UVB-irradiated p53−/− skin. Employing a standard UVB cancer chemoprevention protocol, we demonstrated that CP-31398 is a potent chemopreventive agent in skin. It reduces the growth of UVB-induced cutaneous SCCs and affords protection against cutaneous photo carcinogenesis. In addition, in human epidermoid carcinoma A431 cells carrying a mutation in codon 273, R273H (Arg to His) of the p53 gene that abolishes the ability of p53 to transactivate its downstream target genes, CP-31398 induces p53-dependent cell cycle arrest and apoptosis. CP-31398 also leads to mitochondrial translocation of p53, as well as p53-dependent mitochondrial opening of membrane permeability pore (MOMP), thereby signaling the release of cytochrome c and activation of caspase-3 [35]. This p53 translocation can be inhibited by cyclosporine A (CsA), pointing to a possible molecular crosstalk between the CsA inhibitable mitochondrial permeability transition pore and the p53 system [37]. In an independent study, we also demonstrated that CP-31398 blocks the growth of rhabdomyosar-coma (RMS) cells irrespective of their p53 status (wild-type or mutant). RMS is a commonly occurring soft-tissue sarcoma of childhood for which effective therapeutic options are lacking [38]. The mechanism by which CP-31398 blocks RMS growth involves cell cycle arrest followed by apoptosis in a p53-dependent manner. CP-31398 blocks proliferation in these cells through the co-induction of SOX9 and p21. It also reduces the invasiveness of these tumors by inducing mesenchymal-epithelial transition, ultimately leading to enhanced tumor-free survival of the host animals [38]. These studies suggest that reactivation of p53 may play a role in reversing the aggressiveness of neoplasm. In another study employing intestinal cancer prone APCMIN mice, CP-31398 was found to reduce the growth of spontaneous colon tumors. In this study the authors found that CP-31398 was more effective in the preventative rather than therapeutic mode of action [39]. In an independent study, these authors also showed a positive tumor growth blocking response in the presence of a specific COX-2 inhibitor, celecoxib [40].

b. Ellipticine is another such compound which can enhance sequence specific DNA binding and transcriptional activity of mutant p53 leading to p53-dependent cell cycle arrest and cell death [41]. Ellipticine was initially discovered by analysis of drug sensitive profiles of the panel of NCI's tumor cell lines, showing specificity for p53 mutant carrying cell lines [42]. In a recent study, this small molecule was found to enhance the ability of 5-fluorouracil to deplete cancer stem cell populations [43].

c. In a phenotypic screen of a chemical library of compounds which can preferentially kill cancer cells expressing mutant p53 and have no effects on isogenic cells lacking p53, Bykov et. al. discovered PRIMA-1. This chemical agent was found to restore transcriptional activity of numerous p53 mutant proteins and induce apoptosis. Parenteral administration of this compound was found to suppress the growth of human tumor xenografts [44]. The mechanism of action of PRIMA-1 is not quite clear. However, it involves transcriptional activation of mutant p53 and p53-dependent genes such as PUMA, Noxa and Bax in addition to apoptosis induction [45]. Caspase-2 induction was found to be involved in PUMA-mediated apoptotic cell death in lung, ovarian, and osteosarcoma cells, all carrying a mutant p53 [46]. In addition, JNK survival pathway inhibition by PRIMA-1 has also been demonstrated to be the underlying mechanism of the reduction of breast and colon cell survival [47]. PRIMA-1 was found efficient in killing tumor cells from patients with acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). Its more effective analog PRIMA-1 (also known as APR-246) was found to have a suitable pharmacokinetics and absence of toxic manifestations in animal models suggesting its potential for clinical applications [48].

d. The p53 family member's p63 and p73 contribute to the tumor suppressor functions of p53. These isoforms share many common transcriptional targets with p53 and, as a result, p63 and p73 affect p53-dependent apoptosis and chemosensitivity to cancer cells [49]. It is also known that activation of p73 in human cancer cells lacking p53 produces substantial cytotoxic effects providing a logic for employing p73 as an anti-cancer molecular target [50]. In this regard, a small molecule RETRA was identified as an activator of p73. RETRA activates a number of p53-regulated genes and suppresses the growth of tumor cells carrying mutant p53 [50]. The mechanism of action of RETRA involves release of p73 from its blocking complex with mutant p53 [50]. Interestingly, this agent does not affect normal cells. In this regard, Bell et al described a peptide-dependent pharmacological approach to directly activate p73. This peptide binds with iASPP, a common inhibitor of p53 family proteins, and disrupts the interaction between iASPP and p73. This in turn results in derepression of endogenous p73, which induces p73-dependent cell death and tumor regression irrespective of the presence or absence of wild-type p53 [51].

iii. TARGETING p53 TO REGULATE ENERGY METABOLISM

Investigated long ago by Warburg (1956), the rate of anaerobic lactic acid production in cancer cells is much higher than in normal cells. However, it has recently been linked to a p53-dependent pathway [52]. It has been shown that p53 is involved in the modulation of glycolysis. Pyruvate, the major metabolic product of glycolysis, induces p53 expression [52]. Another link between p53 and aerobic respiration was provided by Maoba et. al. who showed that p53+/+ mice consumed significantly more oxygen and produced more ATP than their p53−/− littermates [53]. Various enzymes involved in glycolysis are also regulated by p53. Type 2 hexokinase, an enzyme responsible for the conversion of glucose to glucose-6-phosphate during the initial reaction of glycolysis, is up regulated by p53 [54]. It has also been shown that this enzyme possesses a p53 response element in the promoter region of its gene [55]. Hypoxia which induces p53 expression also induces type 2 hexokinase [56]. Phosphoglyceratemutase, another enzyme involved in the glycolysis which converts 3-phosphoglycerate to 2-phosphoglycerate during the late stage of glycolysis, is negatively regulated by p53. TP53-induced glycolysis and apoptosis regulator (TIGAR) has recently been discovered to connect p53 with glucose metabolism [57]. TIGAR is similar to proteins of the phosphoglyceratemutase family and shares similarity with bisphosphatase domain of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase [58]. An increase in TIGAR expression results in a decrease in fructose-2, 6-bisphosphatase levels to blunt glycolytic flux. TIGAR also decreases the cellular levels of reactive oxygen species (ROS) during mild cellular stress. Interestingly, ROS can upregulate p53 transcriptional activity thus providing a feedback loop. This mechanism is significant during hypoxic conditions where ROS are required to partially mediate the effects of radiation and anti-cancer drugs [59]. In addition to regulating the proteins involved in mitochondrial apoptotic pathway (intransic) such as Bac, Bcl-2 and PUMA, p53 is considered important in regulating the translocation of proteins localized to the outer surface of mitochondria thus regulating mitochondrial membrane potential [60]. These differences in the energy metabolism of p53 deficient and proficient cells provide a therapeutic opportunity to target specifically p53 deficient cells. However, it remains to be demonstrated whether some of the target proteins in this pathway represent an effective druggable target.

iv. TARGETING P53 AND NUCLEAR REPROGRAMMING

Recently, the presence of non-functional p53 or its absence was shown to facilitate nuclear reprogramming. In this regard, Takaha-shi and Yamanaka reported that overexpression of four transcription factors, Oct4, Sox2, Klf4, and c-Myc, is required to attain the de novo pluripotency of murine and human differentiated cells [61]. This reprogramming of somatic cells highlights a dedifferentiation process resembling tumor formation. It has been shown that p53 acts as a barrier to somatic cell reprogramming [62]. Recently, Sarig et al showed that a mutant form of p53 increases the efficiency of the reprogramming process beyond that facilitated by the absence of p53 alone. In this regard, mouse embryonic fibroblasts (MEFs) derived from p53 R172H-knockin mice were reprogrammed more efficiently than MEFs derived from either wild-type or p53 knockout mice [63]. Hypothetically, this provides a window for gene therapy dependent dedifferentiation of tumor cells into normal or normal appearing cells that may ultimately differentiate and then be eliminated.

iii. CONCLUSIONS AND PROSPECTS

In summary, the major strategies for translating p53 research into the clinic to treat cancer have been focused on developing small molecules that may target mutant p53 and refold it to its wild-type conformation or target molecules that eventually may lead to enhanced accumulation of wild-type p53 [64]. Nonetheless, development of vaccines against p53 if successful in human trials is considered a more versatile approach than the development of small molecules. Both approaches are very appealing but the final outcome in terms of successful cancer therapy is not certain at this stage. According to a recent report, a least 151 trials exploiting the p53 pathway have been conducted [65]. p53 activation in cancers occurring at different anatomical sites does not produce identical therapeutic effects [66]. Studies utilizing genetic approaches revealed that the responses of p53 activation are also dependent on tumor microenvironment that, in part, is controlled by innate immunity [67]. In addition, activation of aberrant oncogenic signaling pathways that drive tumor growth may interfere with p53 activation signaling leading to alterations in final outcome or even in some cases override the tumor growth-halting effect of p53 activation. These effects, in turn, may result in tumor resistance against p53 activating drugs. The success of various strategies for vaccine development has been partial as a significant percentage of patients do not show the desired tumor regression [68]. Current approaches to improve p53 vaccine-based cancer treatment exploit stronger and more correctly polarized responses for the development of both DNA-based and dendritic cell-delivered p53 vaccines. These novel approaches are likely to overcome the existing obstacles in the development of p53 vaccines.

The future prospect for development of p53-based therapeutics lies in identifying novel p53-dependent drugable targets. Most current investigations related to p53-activating small molecules have been conducted either in cell culture systems and/or employing highly immunodeficient murine xenograft models. Use of immune competent murine models that faithfully recapitulate human pathology will be more informative in predicting clinical results. Current genetic models in this regard demonstrate that the outcome of p53 activation is tissue context dependent. However, pharmacological activation of p53 has not been tested from this perspective. Investigations are also needed to unravel the unique mechanisms associated with p53 activation and their biological consequences in terms of invoking crosstalk with the host tissue and regulating tumor microenvironment.

ACKNOWLEDGEMENTS

Grant Support from the following awards, R01 ES015323, R21ES017494, NCI NO1-CN-43300 261200433001C-521958, P30AR050948.

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