Introduction

Pancreatic cancer is the seventh most common cause of death globally and fourth most common cause of deaths in the United States among all type of cancer deaths in 2012, contributing to about 3.3 lakhs pancreatic cancer deaths out of 13 million total cancer deaths per year. Pancreatic cancer most often occurs in the developed countries, where about 70% new cases were reported in 2012 [1–3]. There are many types of pancreatic cancer but the most common type is pancreatic adenocarcinoma (accounting for about 85% of cases). Pancreatic cancer is responsible for about 6% of total cancer-related deaths. The global annual rate of occurrence for pancreatic cancer is about 8/100,000 persons [4]. Pancreatic cancer is difficult to diagnose at an early stage, thus 70–80% patients are diagnosed at advanced or metastatic stages of pancreatic cancer [5]. Pancreatic adenocarcinoma has a very poor prognosis, and thus after diagnosis only about 25% of patients survive for 1 year and about 5% patients will live for 5 years. If the cancers have been diagnosed at an early stage, the 5-year survival rate has been seen to increase from 5 to about 20% [1, 6, 7].

Histone deacetylase inhibitors (HDACi) are an emerging class of anticancer drugs showing prominent antitumor activity by modulating transcriptional events incorporated with cell growth arrest, proliferation, and apoptosis [8]. In the last decade, four different HDACi—vorinostat (SAHA; 2006) and romidepsin (FK228; 2009) for cutaneous T-cell lymphoma (CTCL); belinostat (Beliodaq; Spectrum Pharmaceuticals; 2014) for peripheral T-cell lymphoma (PTCL), and panobinostat (Farydak; Novartis; 2015) for multiple myeloma—were approved by the US-FDA [9–11]. Apart from panobinostat there are many hydroxamic acid derivatives recognized as HDACi, such as resminostat (4SC201), givinostat (ITF2357), abexinostat (PCI-24781), SB939 (Pracinostat), quisinostat (JNJ-26481585), CUDC-101, etc,. and that are under clinical trials for various types of cancer [12].

Panobinostat (Farydak, Novartis Pharmaceuticals) is a member of the hydroxamic acid class of HDACi recently approved by US Food and Drug Administration (FDA) for the treatment of multiple myeloma. It is a colorless, clear, slightly viscous liquid and chemically known as (2E)-N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl] amino]methyl]phenyl]-2-propenamide, administered in both oral and intravenous forms [11, 13]. This nonselective hydroxamic acid-based HDACi has been tested for certain types of cancer and is under clinical trials for several, including CTCL, Hodgkin’s lymphoma, leukemia, prostate, thyroid, breast and other types of hematologic and solid malignancies [14]. Panobinostat is likely the more potent HDAC inhibitor currently in clinical development, with a longer elimination time than others that have been tested. Panobinostat displays prolonged hyperacetylation of the histone protein, which allows intermittent dosing schedules to reduce the challenging thrombocytopenia observed with all HDAC inhibitors. Furthermore, modulation of gene expression through panobinostat is much more prominent in tumor cells than in healthy cells. These facts warrant further investigation of panobinostat in different types of tumors [15]. In this review, we summarize the current preclinical and clinical status of panobinostat in mono and combination therapy along with the rationale for combination therapy in pancreatic cancer.

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Histone, HDACS, and Epigenetic Modulations in Pancreatic Cancer

Histone deacetylases (HDACs) are a distinct class of enzymes capable of regulating gene expression and epigenetic modifications, and they have played an important role in treating pancreatic cancer. Pancreatic cancer proliferation and survival involves both classes I and II HDACs; class I HDACs play a predominant role in tumorogenesis [16]. Several HDACs such as HDAC1, HDAC2, HDAC3, and HDAC7 were found to be overexpressed in pancreatic cancer cell lines. Overexpression of HDAC1 leads to induction of proliferation and dedifferentiation, poor prognosis, repression of promoters of tumor suppressor genes, development of resistance towards cell cycle arrest, growth inhibition, apoptosis, and autophagy. Overexpression of HDAC2 attenuates the apoptosis via interrupting with TRAIL-mediated apoptosis and death-inducing NOXA gene silencing, while overexpressed HDAC7 interrupts apoptosis initiation and malignant progression, and controls angiogenesis through regulation of angiogenic genes in pancreatic cancer cells [17–22]. Apart from overexpressions of HDACs, the expression of TGFBR2—a tumor suppressor gene responsible for silencing E-cadherinis—was found to be reduced alongside increased expressions of SNAIL as well as HDAC1 and HDAC2 (Snail/HDAC1/HDAC2 complex), a combination which promotes the metastatic pancreatic cancer process by suppressing E-cadherin expression via deacetylation of H3 and H4 proteins within the CDH1 promoter [23–26]. The CDH1 further encodes for the E-cadherin, which is downregulated in cancer invasion and metastasis and become an important element in epithelial to mesenchymal transition (EMT) [27].

On the other hand, histone methyl transferases such as EZH2 and SUV39H1 are also involved in tumorogenesis in pancreatic cells. SUV39H1 is involved in trimethylation of H3K9 and subsequent binding by HP1 leading to gene silencing and chromatin repression [28, 29]. Meanwhile, the accumulation of EZH2 is increased, which is associated with acceleration of pancreatic cell proliferation via the downregulation of p27Kip1 (a cell cycle regulator), and thus the depletion of EZH2 may become a target in treating pancreatic cancer [30].

Various studies have demonstrated that expression of miRNAs such as miR-21 is increased, which results induction of proliferation of and invasion by pancreatic cancer cells as compared to control cells [31–33]. The miR-21 has targeted various apoptotic genes such as PDCD4 and PTEN, causing attenuation of apoptosis and induction of tumorogenicity [34]. These observations clearly reveal the importance of histone proteins, HDACs, and epigenetic modulations in pancreatic tumorogenesis.

HDACi and pancreatic cancer

HDACi increased the acetylation of histone and other non-histone proteins, causing alteration in gene expression, angiogenesis, apoptosis, cell-cycle arrest, and metastasis (Fig. 1) [35].

Fig. 1
figure 1

Role and effects of HDACi in pancreatic cancer with their corresponding targets. HIF-1α hypoxia-inducible factor-1 alpha, TRAIL tumor necrosis factor-related apoptosis-inducing ligand, VEGF vascular endothelial growth factor, HSP90 heat shock protein 90, CDK cyclin-dependent kinase, up arrow symbol upregulation, down arrow symbol downregulation

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Role of HDACi in Suppression of Angiogenesis

HDACi play an important role in regulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1alpha (HIF-1α). HIF-1α is able to induce transcription of genes that are involved in cell proliferation and survival. VEGFs are involved in various biological processes including angiogenesis. Treatment with HDACi downregulates the expression of VEGF and HIF-1α, resulting in inhibition of transcriptional activity in pancreatic cancer cell lines [36, 37]. HDACi also inhibit the HDAC6 enzyme, leading to acetylation of heat shock protein 90 (HSP90) and inhibition of its chaperon function, resulting in the degradation of HIF-1α [37, 38]. Additionally, HDACi are also able to induce anti-angiogenesis by inhibiting the proliferation of endothelial cells through decreasing the expression of C-X-C chemokine receptor type 4 (CRCX4) [39–41].

Role of HDACi in Apoptosis and Autophagy

HDACi can exert caspase-dependent and -independent apoptosis through both intrinsic and extrinsic pathways [42, 43]. HDACi mediate with extrinsic apoptosis pathway in pancreatic cancer cells through downregulation of c-FLIP, XIAP, and the induction of FAS, DR5, FASL, and TRAIL (tumor-necrosis factor-related apoptosis-inducing ligand) [44, 45]. As expression of HDAC2 is increased in pancreatic cancer cells, HDACi inhibited HDAC2, leading to pancreatic cancer cell death via TRAIL and death receptor expression [22].On the other hand, upregulation of anti-apoptotic proteins such as XIAP, Mcl-1, and Bcl-2 makes pancreatic cells insensitive to intrinsic apoptosis [46]. HDACi target the intrinsic apoptosis pathway by downregulating the expression of Bcl-2, Bcl-xl, Bcl-w, and Mcl-1 (anti-apoptotic proteins) and upregulating the expression of Bax, Bak, and Bim (pro-apoptotic protein) [42, 47–51].

HDAC inhibitors are also able to induce caspase-independent autophagic cell death without any nuclear fragmentation. Autophagy is a key mechanism of cell death in apoptotic deficient conditions and plays an important role in cell survival during stress conditions such as hypoxia, unfolded protein response, endoplasmic reticulum (ER) stress, nutrient starvation, and treatment of cancers with chemotherapeutic agents. Studies have also revealed that HDACi are capable of generation and intracellular accumulation of the reactive oxygen species (ROS) responsible for the caspase-independent apoptosis in pancreatic cancer cells [20, 36, 52–54, 106].

Role of HDACi in Cell-cycle Arrest

HDACi can induce cell-cycle arrest in pancreatic cancer cells via a p53-independent manner. In pancreatic cancer cells, the cell-cycle progression was modulated by p21, a cyclin-dependent kinase (CDK) inhibitor leading to histone acetylation around the p21 promoter [55]. Treatment with HDACi causes the upregulation of CDK inhibitors such as p21, p19, and p27, and downregulation of the cyclins and cyclin-dependent kinases (CDKs) such as cyclin A, CDK10 etc., which lead to cell-cycle arrest at the G1/S or/and G2/M phase [36, 47, 56–58]. Inhibition of HDACs with selective class I HDACi causes the cell-cycle arrest at G2/M phase. Meanwhile, only a slight impact on the cell cycle was observed with selective class II HDACi. On the other hand, combination of selective class I and class II HDACi have synergistic effects on cell-cycle arrest via mutual p21 upregulation [59]. These studies provide clear evidence that the pan deacetylase inhibitors can be more efficient than selective HDACi in pancreatic cancer cell lines.

Role of HDACi in Metastasis

Epithelial to mesenchymal transition (EMT) is an important regulatory factor involved in tumor invasion and metastasis in pancreatic cancer by loss of cell polarity and cell–cell adhesion properties of epithelial cells. The cellular polarity and cell–cell adhesion of epithelial cells are maintained by a transmembrane glycoprotein E-cadherin. The expression of E-cadherin is suppressed by EMT, leading to metastasis in pancreatic cancer patients with poor survival. The HDACi play their antimetastatic activity by changing the EMT into MET (mesenchymal to epithelial transition). Studies have shown that treatment with HDACi enhanced the expression of E-cadherin in pancreatic cancer cell lines. It was also reveals that transcriptional factor ZEB1 linked with E-cadherin promoter is responsible for HDAC expression, resulting in histone deacetylation and E-cadherin suppression. Thus, HDACi like vorinostat can downregulate the ZEB1 and upregulate the expression of E-cadherin in pancreatic cancer cell lines [60–65]. On the basis of these facts, it is anticipated that HDACi are able to suppress the metastasis in pancreatic cancer cell lines.

General Pharmacokinetic and Pharmacology of Panobinostat

Pharmacokinetics of Panobinostat

Absorption

According to Biopharmaceutical Classification System, panobinostat is classified as a class I drug showing high solubility and permeability, but its bioavailability is not affected by food materials [66]. A dose-dependent increase in the area under curve (AUC) and C max is observed in oral and intravenous administration of panobinostat with T max of approximately 1h, but elimination time (T 1/2) ranged between 8 and 18 h [13, 67–72]. On the other hand, reduced C max and slightly prolonged T max are observed upon panobinostat administration after food intake. The rate of absorption is influenced by food material but the extent of absorption has not altered. As the overall absorption of panobinostat is not affected by food, it can be administered with or without food [66]. Co-administration of panobinostat with ketoconazole causes an increased C max and AUC of panobinostat without any marginal change in T max or T 1/2 [73]. Additionally, normal, mild, and moderate hepatic impairments cause the increased systemic level of panobinostat in cancer patients [74].

Metabolism

Panobinostat is metabolized by various pathways such as oxidation, reduction, hydrolysis, and glucuronidation reactions. Oxidative metabolism of panobinostat is mainly carried out by human cytochrome P450 enzymes such as CYP2D6, CYP3A4, and CYP2C19. More than 77 metabolites of panobinostat have been recognized in which about 40 metabolites are detected in circulating plasma. These metabolites are excreted through both feces and urine. About 44–77% metabolites of total oral administered panobinostat are observed in feces and 29–51% are excreted in urine while ≤3.5% metabolites are remained unchanged in feces, demonstrating good oral absorption of panobinostat [73, 75, 76]. The pharmacokinetic profile of panobinostat and BJB432 (major metabolite of panobinostat) are not much affected by renal impairment and its severity of diseased conditions [77].

Adverse Effects

The most common toxicities of panobinostat are related to the gastrointestinal, constitutional, and hematological system. Treatment with panobinostat involves dose-dependent grade 1–4 toxicities such as nausea, vomiting, fatigue, diarrhea, and thrombocytopenia. In several cases, dose-dependent cardiac toxicity such as QT prolongation is also reported with panobinostat treatment [78–84]. In addition, normal, mild, and moderate severities of renal and hepatic impairments do not have much influence on the safety profile of panobinostat in advanced cancer patients [74, 77].

General Pharmacology of Panobinostat

Panobinostat is a nonselective histone deacetylase inhibitor having potential HDAC inhibitory activity against all Class I, II, and IV at nanomolar concentrations. Panobinostat interferes with histone and non-histone proteins such as H3, H4, HIF-1α (hypoxia-inducible factor 1 alpha), β-catenin, α-tubulin, Chaperons (HSP90), estrogen receptor (ER α), androgen receptor (AR), signaling mediators (Stat3, Smad7), DNA repair proteins (Ku70), retinoblastoma protein (pRb), etc., leading to alterations in transcriptional factors (p53, E2F, NF-κB, c-Myc) [85–87]. Acetylation of α-tubulin is directly related to the inhibition of HDAC6. These effects were cumulatively related to the cell-cycle arrest at the G2-M phase. A delay in the G2phase and abnormal mitotic progression is observed with panobinostat treatment, which is mediated by the activation of PLK1 and Cyclin B1 expression and suppression of E2F1 [39, 88]. Further, Hsp90 acetylation induced by panobinostat treatment causes a decrease in the association of Hsp90 with other chaperone proteins (e.g., Akt, EGFR, STAT3, c-Src) and disrupted Hsp90 chaperone function, resulting in oncogenic HSP90 client protein degradation [89, 90]. The antiangiogenesis properties of panobinostat are associated with the inhibition of CXCR4, HIF-1α, and VEGF-induced signaling in human endothelial cells [39].

Treatment with panobinostat involves the induction of autophagy via a death-associated protein kinase (DAPK)-dependent manner, while apoptosis is associated with a DAPK-independent manner in human colon tumor cells [91]. Panobinostat also interferes with both intrinsic and extrinsic apoptosis pathways by enhancing TRAIL-mediated cytotoxicity via decreasing the expression of Bcl-xl, Bcl-2, and XIAP, and increasing the expression of Bim, BAX, and BAK (pro-apoptotic proteins) [92–95]. Apoptosisis was also induced by the generation of ROS with panobinostat alone or in combination with other drugs [96]. Panobinostat selectively induces apoptosis in cancer cells without having a marked effect on normal human epithelial cells, fibroblasts, and peripheral blood mononuclear cells [97].The antitumor properties of panobinostat and other HDACi are also mediated by the enhanced numbers of activated T cells, systemic cytokine responses, and regulatory T cell ratio [98, 99].

Therapeutic efficacy of panobinostat in pancreatic cancers

Panobinostat: Mono-therapy in Pancreatic Cancer

Panobinostat induces pancreatic tumor cell death in a dose-dependent manner. It significantly reduces tumor growth in subcutaneous xenograft mouse model at the micromolar range with minimal toxicity toward normal cells. Panobinostat is found to be as equipotent as gemcitabine in terms of tumor size reduction and more effective than TSA in pancreatic cancer cell lines. Both panobinostat and TSA are able to induce the death of pancreatic tumor cell lines by apoptosis. Panobinostat has been found to induce acetylation of H4 histone protein and promote the expression of p21WAF−1/CIP−1, ultimately leading to cell-cycle arrest at the G2/M-checkpoint of cancer cell death. It also decreases cellular levels of HDAC1, HDAC2, and HDAC3 as well as SIRT1 in the case of SOJ-6 pancreatic cancer cells compared to control cells, but the level of SIRT2 expression can be up- or downregulated depending upon the cell lines used. Therefore, translational regulation of the HDAC encoding genes are dependent on the cell lines considered during translation [100, 101]. Treatment with panobinostat also induces pH2AX (a biomarker of DNA double-strand breaks) and suppresses checkpoint kinase 1 (CHK1) [16]. Furthermore, panobinostat is able to induce apoptosis by potentiating TRAIL-induced apoptosis and cFLIP degradation even in TRAIL-resistant cells. Treatment with panobinostat increases the level of ubiqutinated c-FLIP and increases degradation of c-FLIP mediated by ubiqutin/proteasome, leading to downregulation of c-FLIP. Thus, PAN is able to potentiate TRAIL-induced apoptosis in pancreatic tumor cells [44].

Chien et al. demonstrated the potency of SAHA, belinostat, and panobinostat in pancreatic cancer cell lines and determined the EC50 values, showing that belinostat was more potent than SAHA in Panc0327, Panc0403, and MiaPaCa2 pancreatic cancer cell lines. The EC50 value of belinostat was found to be in the micromolar range while panobinostat was active in the nanomolar range against 14 different pancreatic cancer cell lines [36]. Preclinical study of panobinostat in a pancreatic cancer xenograft mouse model shows that it is as equipotent as gemcitabine in terms of tumor growth reduction [100]. As among all HDACi, panobinostat is found to be more active and as equipotent as gemcitabine in pancreatic cancer cells, and thus it should be explored in clinical development in combination therapy with other antitumor agents.

Panobinostat: Combination Therapy in Pancreatic Cancer

Panobinostat in Combination with Gemcitabin

The anticancer activity of panobinostat towards pancreatic cancer was first tested by Haefner et al. in 2008. They showed that a combination of panobinostat and gemcitabine significantly reduced tumor mass in vivo in nude mice models, but apoptosis was slightly increased and there was no significant reduction of cell proliferation. They found that panobinostat is more efficient than gemcitabine and increases the potency of gemcitabine in combination therapy [101]. A phase I study was performed to determine the safety and tolerability of panobinostat and gemcitabine in combination therapy. The oral administration of panobinostat 30 mg BIW and gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 every 28 days showed grade 4 thrombocytopenia in 2/3 patients. However, panobinostat 10 mg TIW for 2 weeks and gemcitabine 800 mg/m2 on days 1 and 8 every 21 days was well tolerated in 5/6 patients with relatively low levels of grade 4 neutropenia and thrombocytopenia toxicities (35% and 18%, respectively). No patients experienced grade 2 or grade 3 QTcF prolongation. The recommended doses for further study are panobinostat 10 mg TIW orally for 1 week along with gemcitabine 800 mg/m2 IV on days 1 and 8 every 21 days. In all instances, dose-limiting toxicities occurred due to myelosuppression during the treatment at all dose levels. Mild to moderate toxicities related to treatment are nausea, vomiting, constipation, diarrhea, anorexia, fatigue, and rashes (Table 1) [14].

Table 1 Preclinical and clinical prospective of panobinostat in pancreatic cancer
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Panobinostat in Combination with Bortezomib

Treatment of pancreatic cancer with bortezomib, a proteasome inhibitor, results in the formation of aggresome (aggregates of ubiquitin-conjugated proteins) in both in-vivo and in-vitro models. On the other hand, HDACs are known to regulate the functions of histone and nonhistone proteins through the promotion of ubiquitin-dependent proteasomal degradation, thus, inhibition of aggresome formation via HDACi treatment can potentiate the effect of bortezomib. Panobinostat (20 mg orally once daily on days 1, 3, 5, 8, 10, and 12 followed by nine days of rest) in combination with bortezomib 1.3 mg/m2 IV BIW for every 21 days was administered in seven patients in phase II clinical trials. Unfortunately, the study was terminated due to lack of treatment response and grade 4 thrombocytopenia and diarrhea in phase II clinical trials (Table 1) [102].

Panobinostat in Combination with BEZ235

The K-RAS and PI3K/AKT/mTOR signaling pathways play an important role in human pancreatic ductal adenocarcinoma (PDAC). Thus, targeting these pathways or mediators may become an effective means of treatment of PDAC. Therefore, Venkannagari et al. combined panobinostat with dual PI3 K/mTOR inhibitor BEZ235 in a preclinical nude mouse model against pancreatic cancer cells. BEZ235 treatment in pancreatic cells inhibited the activity of PI3K, TORC1, and TORC2, causing a reduction in phosphorylated AKT, 4EBP1, and p70S6 K, and leading to the induction of BIM. This led to decreases in cell proliferation and cell-cycle arrest of pancreatic cancer cells. On the other hand, treatment with panobinostat inhibited phosphorylated AKT, leading to nuclear localization of FOXO3A. It also inhibits TORC1 activity leading to reduction in phosphorylated 4EBP1 and p70S6 K, ultimately inducing expression of p21, p27, and pro-apoptotic proteins (BIM and BAK). Co-treatment with BEZ235 and panobinostat caused greater induction of BIM and increased cell death of pancreatic cancer cells. Treatment with panobinostat (10 mg/kg IP TIW), BEZ235 (25 mg/kg, PO) and a combination of panobinostat and BEZ235 for 3 weeks in the preclinical nude mouse model showed marked difference in mean tumor volume in combination therapy as compared to use of a single agent alone. Thus, combination of panobinostat and BEZ235 synergistically potentiate the antitumor activity and induced apoptosis in PDAC cells (Table 1) [103].

Panobinostat in Combination with MK-1775

Wang et al. studied the combination of Wee1 inhibitor, MK-1775, and the pan-deacetylase inhibitor panobinostat in preclinical xenograft mouse model pancreatic cells and demonstrated the rationale behind the combination therapy. MK-1775 induces DNA damage by increasing H2AX phosphorylation and activating CDK1/CDK2. It also activates CDK-dependent CHK1 and ATM/ATR. In addition, MK-1775 increases p-CHK1, indicating activation of the CHK1 pathway. Activation of CHK1 results in inactivation of CDC25s, causing a decrease in active CDK1/2, cell-cycle arrest, DNA repair, and cell survival. Furthermore, activated CHK1 directly increases the activity of Wee1. These facts demonstrate the mechanism of resistance to treatment with MK-1775. On the other hand, treatment with panobinostat downregulates the CHK1 or inactivates the CHK1 pathway and activates CDK1 and CDK2, thus inducing DNA damage and subsequently apoptosis. Therefore, combining panobinostat with MK-1775 can prevent activation of CHK1 leading to an increase in DNA damage and cell death. Further, panobinostat treatment also increases pH2AX levels, causing the DNA damage. Treatment with panobinostat (10 mg/kg IP BIW once daily), MK-1775 (20 mg/kg O BIW twice daily), and a combination for 3 weeks in a preclinical pancreatic cancer xenograft mouse model showed a significant delay of tumor growth: 58.7% with combination therapy as compared to 30.9% with MK-1775 and 37.8% with panobinostat as a single agent alone [104]. These facts clearly provide the evidence for using a combination of panobinostat with MK-1775 in pancreatic tumor cells in preclinical models, and supported the fact that combination therapy should be promoted in the clinical development for this deadly disease.

Panobinostat in Combination with IMC-RON8

The expression of Ron (Recepteur d’origine nantais) rarely takes place in normal pancreatic cells, but it is overexpressed in cancerous pancreatic cells. The activation and overexpression of Ron is mediated by the macrophage stimulating protein (MSP), resulting in the activation of tumorogenesis pathways. Thus, Ron may become an important therapeutic target for the treatment of pancreatic cancer. On the basis of this assumption, the first Ron monoclonal antibody, IMC-RON8, has been entered into clinical trials for targeting overexpression of Ron. IMC-RON8 downregulates the expression of Ron, and inhibits MSP-stimulated Ron activation, leading to attenuated phosphorylation of Akt and ERK and expression of survivin mRNA. These effects simultaneously reduce MSP-induced pancreatic cell proliferation. On the other hand, panobinostat decreases Ron expression, pAkt, survivin, and XIAP in pancreatic cancer cells leading to enhanced cell apoptosis. Interestingly, treatment with panobinostat causes reduction in colony formation in cells having low Ron levels to a greater extent than cells having higher levels of Ron. Thus, combination therapy of IMC-RON8 with panobinostat sensitizes the pancreatic cancer cell lines to reduce the numbers and size of colonies and produce more prominent effects than mono therapy in a preclinical study. The combination therapy further reduces the expression of Ron, phosphorylated Akt, and increases the cleavage of PARP as compared to a single treatment. These results suggest a novel and potential combination approach in the treatment of pancreatic cancer and should be explored in clinical developments [105]. The current clinical status of panobinostat and its combination therapy is undergoing trials (Table 1) and should be further explored in the future for the treatment of pancreatic cancer.

Concluding Remarks and Future Prospective

In conclusion, we have gone through comprehensive studies supporting the role of HDACs in pancreatic carcinoma and shown the aberrant overexpression of different HDACs such as HDAC1, HDAC2, HDAC3, and HDAC7. This aberrant overexpression may contribute to carcinogenesis by unbalancing the histone acetylation and deacetylation, leading to uncontrolled cell growth and proliferation in pancreatic cancer cells. Thus, inhibiting histone deacetylase enzymes may become an important therapeutic target to treat pancreatic cancer patients.

Panobinostat is a new anticancer agent of histone deacetylase inhibitor that inhibits tumor cell growth, proliferation, and differentiation, ultimately leading to cell-cycle arrest. As histone acetylation is a fundamental function of panobinostat, it mediates its biological effect through the regulation of gene expression via direct histone hyperacetylation. Moreover, it also mediates the antitumor activity by acetylation of non-histone proteins, indicating that it could have a much broader effect on cellular physiology. Apart from hyperacetylation, as a pan-deacetylase inhibitor panobinostat can activate the death-receptors, extrinsic-intrinsic apoptotic pathways, and autophagy-mediated cell death, concomitant with upregulation of transcriptional pro-apoptotic genes and downregulation of pro-survival genes.

As panobinostat is a nonselective histone deacetylase inhibitor, it can target different classes of HDACs. During the exhaustive study we have found that treatment of pancreatic cancer with selective HDAC class inhibitors have less potency as compared to a combination of selective class inhibitors indicating that non-selective inhibits can be more potent that selective ones. In this review, we have also shown that treatment of pancreatic cancer with panobinostat alone or in combination with other drugs such as gemcitabin, bortezomib, BEZ235, MK-1775, and IMC-RON8 are highly efficient in preclinical models. The phase I study of panobinostat and gemcitabin showed dose-limiting toxicities in pancreatic cancer patients while a combination of bortezomib was terminated due to lack of treatment response. As many signaling pathways are involved in pancreatic tumorogenesis and interlinked to each other by several mediators, it may be more beneficial to combine the inhibitors of these signaling pathways. On the basis of this assumption, various preclinical studies have been performed in combination of panobinostat with BEZ235 (a RAS and PI3 K/AKT/mTOR inhibitor), IMC-RON8 (Ron monoclonal antibody), and MK-1775 (Wee1 Inhibitor), indicating pronounced antitumor activity in pancreatic cancer preclinical models, and should be further explored in clinical trials for development of new effective combinations.