The natural cAMP elevating compound forskolin in cancer therapy: Is it time? †

Luigi Sapio1, Monica Gallo2, Michela Illiano1, Emilio Chiosi1, Daniele Naviglio3, Annamaria
Spina1 and Silvio Naviglio1*

1Department of Biochemistry, Biophysics and General Pathology. Second University of Naples, Medical School, Via L. De Crecchio 7, 80138 Naples, Italy.
2Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, via Pansini, 5, 80131 Naples, Italy.
3Department of Chemical Sciences, University of Naples Federico II, via Cintia 21, 80126 Naples, Italy

*Correspondence to: Silvio Naviglio, email: [email protected]

Keywords: forskolin, cyclic AMP, cancer therapy, naturally occurring molecules, medicinal plants

†This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: [10.1002/jcp.25650]

Received 11 September 2016; Revised 4 October 2016; Accepted 12 October 2016
Journal of Cellular Physiology
This article is protected by copyright. All rights reserved
DOI 10.1002/jcp.25650

ABSTRACT

Cancer is a major public health problem and the second leading cause of mortality around the world. Although continuous advances in the science of oncology and cancer research are now leading to improved outcomes for many cancer patients, novel cancer treatment options are strongly demanded. Naturally occurring compounds from a variety of vegetables, fruits and medicinal plants have been shown to exhibit various anticancer properties in a number of in vitro and in vivo studies and represent an attractive research area for the development of new therapeutic strategies to fight cancer.
Forskolin is a diterpene produced by the roots of the Indian plant Coleus forskohlii. The natural compound forskolin has been used for centuries in traditional medicine and its safety has also been documented in conventional modern medicine. Forskolin directly activates the adenylate cyclase enzyme, that generates cAMP from ATP, thus raising intracellular cAMP levels.
Notably, cAMP signaling, through the PKA-dependent and/or independent pathways, is very relevant to cancer and its targeting has shown a number of antitumor effects, including the induction of mesenchymal-to-epithelial transition, inhibition of cell growth and migration and enhancement of sensitivity to conventional antitumor drugs in cancer cells.
Here, we describe some features of cAMP signaling that are relevant to cancer biology and address the state of the art concerning the natural cAMP elevating compound forskolin and its perspectives as an effective anticancer agent. This article is protected by copyright. All rights reserved

INTRODUCTION

Cancer is a highly heterogeneous and complex disease (Costello et al., 2012; Hanahan et al.,2011). Remarkably, cancer figures among the leading causes of morbility and mortality worldwide and the number of new cases is expected to rise by more than 50% over the next two decades (Fitzmaurice et al., 2013). Although, according to a recent analysis of 28 cancer groups in 188 countries, the death rates from cancer are falling in many countries, overall the cancer survival rate after 5 years is still low, approximately of 60% (Fitzmaurice et al., 2015; Stewart et al., 2014). Thus, new approaches to the treatment of cancer are needed.
Recently, combination chemotherapy has received more attention in order to find compounds that could increase the therapeutic index of clinical anticancer drugs (Turek et al., 2016). In this regard, naturally occurring molecules with antitumor activity and with the least toxicity to normal tissues are proposed as possible intriguing candidates to be investigated for their synergistic efficacy in combination with conventional antineoplastic drugs (Naviglio et al., 2013; Shanmugam et al., 2016). In addition, the concept of chemoprevention is increasingly gaining attention in cancer. At this regard, cancer chemoprevention by natural compounds, especially phytochemicals, minerals, and vitamins, has shown promising results against various malignancies in numerous studies under both in vitro and in vivo conditions (Shanmugam et al., 2016; Nobili et al.,2009).
Overall, in the development of bioactive chemical, natural products from medicinal plants have a rich and long history and represent a very interesting research area for novel therapeutic anticancer strategies (Greenwell et al., 2015; Millimouno et al., 2014).
Among the natural compounds from medicinal plants, forskolin can be suggested as one of the most interesting molecules to possibly use in cancer therapy.
Forskolin is a diterpene produced by the roots of the Indian plant Coleus forskohlii (Fig. 1) (Kanne et al., 2015). Notably, the natural compound forskolin has been used for centuries in traditional medicine, is considered to be affordable and its safety has also been documented recently in modern medicine ( Ammon et al., 1985; Godard et al., 2005; Henderson et al., 2005; Loftus et al., 2015). Forskolin directly activates the adenylate cyclase enzyme, that generates cAMP from ATP, thus raising intracellular cAMP concentrations (Seamon et al., 1981).
Importantly, targeting cAMP levels and signaling has been shown to result in a number of relevant anticancer effects, such as the induction of mesenchymal-to-epithelial transition, the enhancement of the sensitivity to conventional antineoplastic drugs and the inhibition of proliferation, motility and migration in many types of cancer cells ( Pattabiraman et al., 2016; Follin-Arbelet et al., 2015; Perez et al., 2016; Naviglio et al., 2010; Burdyga et al., 2013; Dong et al., 2015).
Below, after describing briefly some features of cAMP signaling relevant to cancer biology, we address the state of the art concerning forskolin and discuss its perspectives as a natural cAMP elevating agent to be clinically used as an anticancer compound.

A GLANCE AT cAMP SIGNALLING

Adenosine 3’5’-cyclic monophosphate (cyclic AMP, cAMP) was first identified as a small
intracellular heat-stable factor mediating the effect of glucagon on the phosphorylation status of glycogen phosphorylase in the 1950s. Thereafter, the concept of cAMP as an important second messanger for many extracellular signaling molecules rapidly developed (Beavo et al., 2002).
cAMP is generated by adenylate cyclase enzymes, ACs, from the conversion of ATP to cAMP and pyrophosphate in every cell and can be induced more than twenty fold upon activation of ACs by extracellular signals (Hanoune and Defer, 2001). Ten AC isoforms have been cloned and characterized in mammals; they are represented by 9 transmembrane AC isoforms (AC1 up to AC9) and one soluble AC isoform (AC10) (Sabbatini et al., 2014).

Degradation of cAMP is mediated by cAMP phosphodiesterases, PDEs, that hydrolyze cAMP into adenosine 5’-monophosphate and this event is important for controlling cAMP resting state levels (Omori and Kotera, 2007). So, intracellular levels of cAMP result from the controlled balance between the activities of synthesis and degradation by adenylate cyclases and cAMP phosphodiesterases, respectively. Since a large number of hormones, neurotransmitters and other signal molecules use cAMP as an intracellular mediator, the rate of cAMP production and degradation is sensitive to a wide range of extracellular and intracellular signals, and cAMP can directly regulate numerous cell functions ( Gancedo, 2013). Some heterotrimeric G-protein coupled receptors, such as the nicotinic acetylcholine receptors, beta adrenergic receptors, or adenosine receptors, are known to activate adenylyl cyclase enzymes, resulting into an increased cAMP production (Dang et al., 2016; Tang et al., 2013; Di Virgilio et al., 2016). However, agents that directly activate adenylyl cyclases such as forskolin (we extensively describe below) or inhibit PDE such as theophylline and caffeine bypass heterotrimeric receptor-coupled activation of signaling pathways and lead to an elevation of intracellular cAMP levels, too (Seamon et al., 1981; Seamon et al., 1983; Francis et al., 2011).
Within each cell, cAMP may activate different proteins. For example cAMP may affect directly the ion channels (Biel, 2009). An important additional effector system for cAMP is represented by the exchange proteins directly activated by cAMP 1 and 2, Epac1 and Epac2, also named cAMP-GEFI and -II (Chen et al., 2014). These guanine nucleotide exchange factors (GEFs) are specific activators of the small GTPase Rap1. The cAMP-binding domain of Epac can bind one moiety of cAMP, resulting in a conformational change of Epac enabling the protein to bind to and activate Rap1 ( Gloerich and Bos , 2011). In addition to the ion channels and Epac, there is a general agreement that the main intracellular target for cAMP in mammalian cells is the cAMP-dependent protein kinase (PKA; EC 2.7.1.37) (Turnham and Scott, 2016).
The existence of different cAMP downstream effectors and some features of PKA signaling pathway may contribute to explain how differential discrete effects of cAMP can be obtained (Skalhegg and Tasken, 2000). An additional important concept is that cAMP levels can change and cAMP signaling can occur very locally, respectively (Lefkimmiatis and Zaccolo, 2014).
cAMP, either via a PKA-dependent or PKA-independent manner, affects numerous cellular functions such as metabolism, gene expression, ion channel activation, cell proliferation, differentiation, apoptosis, and is considered very relevant to cancer (Beavo and Brunton, 2002; Gancedo, 2013). Moreover, the cAMP signaling interacts with other intracellular signaling pathways, including cytokine and Ras-Raf- Erk pathways (Spina et al., 2013; Follin-Arbelet et al., 2013; Tai et al., 2014; Cheng et al., 2016; Park and Juhnn, 2016). Notably, these signaling connections also play an important role in cancer biology and a combined blockade of such signaling pathways is considered a relevant strategy for therapeutic intervention to fight cancer (Awada and Aftimos, 2013; Kidger and Keyse, 2016; Indovina et al., 2016).

FORSKOLIN AS AN OLD NATURAL OCCURRING cAMP ELEVATING COMPOUND: AN OVERVIEW

Forskolin is a naturally derived diterpenoid extracted from the roots of the Indian plant Coleus
forskohlii (Fig. 1) (Seamon et al., 1981; Valdés et al., 1987). Coleus forskohlii is a perennial
member of the mint or Lamiaceae (also known as Labiatae) family that was first discovered in the lower elevations of India (Alasbahi and Melzig, 2010; Murugesan et al., 2012). Since ancient times, this plant has been used in Hindu Ayurvedic preparations as an herbal medicine to treat various disorders such as hypertension, congestive heart failure, respiratory disorders, angina, asthma, psoriasis, eczema, colic, painful urination, insomnia, convulsions and even for prevention of cancer metastases (Murugesan et al., 2012; Kavitha et al., 2010; Sharma and Vasundhara, 2011). Notably, all pharmacological activities related to Coleus forskohlii are mainly due to forskolin that is the primary constituent of clinical interest in this plant (Valdés et al., 1987; Alasbahi and Melzig,

2010; Murugesan et al., 2012; Kavitha et al., 2010; Sharma and Vasundhara, 2011; Wagh et al., 2009).
More in details, forskolin is a labdane diterpene which is derived as an active alkaloid from the roots of C. forskohlii, discovered in the 1970s (Ammon and Müller, 1985; Seamon et al., 1981; Murugesan et al., 2012; Kavitha et al., 2010; Sharma and Vasundhara, 2011; Wagh et al., 2009).
Its chemical name is 7beta-Acetoxy-8, 13-epoxy-1a, 6β, 9a-trihydroxy-labd-14-en-11-one. Its
molecular weight is 410.5 g/mole (anhydrous) and molecular formula is C22 H34 O7. Forskolin
appears as an off-white crystalline solid; having λ-max at 210 nm, 305 nm and its melting point is 228°C-230°C; it is soluble in DMSO, ethanol, methanol and dichloromethane. However, it may be dissolved in 2% ethanol in water, by dissolving it first in ethanol and then subsequently diluting this solution with water (Wagh et al., 2009; Wagh et al., 2012).
Forskolin is a largely known potent, rapid and reversible stimulator of adenylate cyclase activity and consequently a very effective cAMP elevating agent (Fig.2).
Forskolin activation of adenylate cyclase occurs primarily via a direct action of the diterpene on the catalytic subunit of adenylate cyclase enzyme without interacting with cell surface receptors (Seamon et al., 1981; Laurenza et al., 1989; Pinto et al., 2008). Forskolin has been shown to increase cAMP formation in a variety of mammalian membranes, broken cell preparations and intact tissues, without hormonal activation of adenylate cyclase. cAMP elevation by forskolin in turn has been reported to inhibit basophil and mast cell degranulation and histamine release, to have a positive inotropic action on cardiac tissue, to lower the blood pressure and the intraocular pressure, to inhibit platelet aggregation, to promote vasodilation, bronchodilation, to increase thyroid hormone production and release and to stimulate lipolysis in fat cells (Lindner et al., 1978; Dubey et al., 1981; Tsukawaki et al., 1987; Marone et al., 1987; Caprioli and Sears,1983; Haye et al., 1985; Litosch et al., 1982; Burns et al., 1987; Wysham et al., 1986; Lichey et al., 1984).
In addition to its intracellular cAMP-elevating activity, it has been shown that forskolin is able to inhibit the binding of platelet-activating factor (PAF), independently of cAMP formation and to have an effect on some membrane transport proteins and to inhibit glucose transport in erythrocytes, adipocytes, platelets, and other cells ( Wong et al., 1993; Yajima et al., 1995; Agarwal and Parks, 1985 ). Forskolin has also been reported to increase cellular acetylcholinesterase and protect neuronal cells from organophosphate toxicity (Curtin et al., 2006).
Notably, forskolin has been clinically used for a variety of conditions including glaucoma, asthma, and heart failure, and more recently obesity (Fig.2).
As far as glaucoma concerned, forskolin reduces the intraocular pressure (IOP) by reducing aqueous humor inflow with no change in outflow facility. Reduction in IOP by forskolin has been studied with animals like monkeys, rabbits and also in healthy human volunteers (Caprioli and Sears,1983;Pescosolido,2010).
The forskolin eye drops have crossed all clinical trial phases and forskolin is a wonder drug with a proven antiglaucoma drug candidature. However, there is a need to undergo further human volunteer studies for newly developed ophthalmic dosage form and drug delivery systems (Wagh et al., 2012).
Limited single-blinded clinical studies have been conducted with oral and inhaled forskolin in patients with asthma and in healthy volunteers. Oral forskolin performed better than sodium chromoglycate in preventing asthma attacks in children and adults with mild/moderate persistent asthma, whereas inhaled forskolin was similar to beclomethasone in lung function improvement (Huerta et al., 2010; González-Sánchez et al., 2006; Bauer et al., 1993 ). Also when administered intravenously, forskolin had a clear bronchodilation effect and no adverse events were described (Wajima et al., 2002; Wajima et al., 2003).
As above reported, forskolin also benefits cardiovascular health due to its inotropic, anti- inflammatory and antiplatelet properties (Lindner et al., 1978; Baumann et al., 1990; Christenson et al., 1995; Hayashida et al., 2001).
Recently, 6-[3 (dimethylamino)propionyl]forskolin, a water-soluble forskolin derivative with high selectivity for type 5 (cardiac) adenylyl cyclase was developed and has been used in the treatment

of acute heart failure (Alasbahi and Melzig, 2010; Pinto et al., 2008; Kikura et al., 2004).One study found also intra-arterial forskolin daropate to be an effective treatment for cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage ( Suzuki et al., 2010).
Moreover, treatment of uropathogenic E.coli-infected mice with forskolin resulted in reduced number of bacteria via cyclic AMP-regulated exocytosis (Bishop et al., 2007).
In addition, topical application of forskolin, which is a skin-permeable compound, has been shown to promote UV-independent production of eumelanin in an MC1R-defective fair-skinned animal model, resulting in robust UV protection by interfering with epidermal penetration of UV photons (D’Orazio et al., 2006; Prunier et al., 2012).
As far as possible drug interactions concerned, since forskolin may have additive hypotensive effect with beta-blockers, vasodilators, calcium channel blockers, etc. the decrease in needed dosage of such drugs may occur due to concurrent use of forskolin. Moreover, since it inhibits platelet aggregation and clotting, the effect of anti-clotting drugs like warfarin, aspirin, anoxaparin, may be enhanced by the forskolin. Moreover, it has been described that forskolin can induce the expression of cytochrome P450 3A (CYP3A) and can potentially increase the metabolism of drugs that are substrates of related microsomal enzymes (Dowless et al., 2005; Ding and Staudinger, 2005; Virgona et al., 2012; Hebbani Nagarajappa et al., 2015) .
In addition, as warnings and contraindications of forskolin it is recommended to avoid its use in the patients with ulcers and in patients with polycystic kidney disease as it may increase acid levels and have a role in promoting cyst enlargement, respectively (Hersey et al., 1983; Putnam et al., 2007). By the way, Coleus forskohlii is considered to have an excellent safety profile and generally has been shown without significant toxicity and side effects in patients.
As reported above, forskolin (or its water-soluble derivative colforsin) has been tested in several clinical settings including cardiovascular diseases, psychiatric disorders and asthma (Wajima et al., 2003; Kikura et al., 2004; Bersudsky et al., 1996).
Interestingly, forskolin is one of the commercially important herbal ingredients for weight loss dietary supplements in the global market (Kanne et al., 2015; Kavitha et al., 2010; Wagh et al., 2009). Its favorable effects on body fat management have been clearly reported (Haye et al., 1985; Litosch et al., 1982; Burns et al., 1987; Shivaprasad et al., 2014) and clinical studies with oral administration of forskolin for up to 50 mg/day as a weight loss agent have not shown relevant side effects in patients (Godard et al., 2005; Henderson et al., 2005; Kavitha et al., 2010; Sharma and Vasundhara, 2011; Wagh et al., 2009; Wagh et al., 2012; Hebbani et al., 2015; Loftus et al., 2015).

FORSKOLIN AND CANCER

In different studies, forskolin has been found to inhibit the growth of the human gastric cancer cell lines by decreasing the activity and expression of protein kinase C and of some oncogene such as Ha-ras and c-jun proteins (Piontek et al., 1993; Guan et al., 1995; Wang et al., 2003). Interestingly, it has been also shown that forskolin inhibited pulmonary tumor colonization and metastasis in mice (Agarwal and Parks, 1983 ).
Moreover, forskolin prevented the growth and induced apoptosis of myeloid and lymphoid cells and has been described also to inhibit the cytokine mediated colony formation and proliferation of CD34+ bone marrow cells (NBMCD34+) (Gützkow et al., 2002; Neviani et al., 2005).
A mixture containing the calcium channel blocker carboxyamidotriazole and cAMP elevating agents, including forskolin, was found to exhibit synergistic antitumor effects and to inhibit the proliferation of tumor cells (Zhang et al., 2005). Accordingly, addition of cyclic nucleotide phosphodiesterase type 4 rolipram to a low dose of forskolin potentiated the growth inhibition induced by forskolin and caused complete growth cessation of chemoresistant KM12C colon cancer cells (McEwan et al., 2007).
On the other hand, pharmacologic stimulation of cAMP using forskolin has been recently described to protect the skin against UV injury and UV-induced carcinogenesis and proposed as a potential

UV-protective strategy in individuals who are fair-skinned, sun-sensitive and melanoma prone
(Amaro-Ortiz et al., 2014). Interestingly, forskolin, as well as other cAMP elevating agents, including PDE inhibitors and cell permeable cAMP analogs, causes an inhibition of cell motility, movement, and migration in a wide range of cancer cells (Burdyga et al., 2013; Dong et al., 2015; Ou et al., 2014).
In agreement with the above studies, previously, in different studies we demonstrated that in MDA- MB-231 triple negative breast cancer cells, forskolin inhibits basal and leptin-induced proliferation and migration by inhibiting and completely abrogating ERK1/2 and STAT3 phosphorylation in response to leptin, respectively. Very surprisingly, we provided evidence that when cAMP levels are increased upon forskolin treatment, leptin drives cells towards apoptosis associated with a marked decrease of Bcl2 protein levels and accompanied by down-regulation of protein kinase A (PKA). In addition, we also found that the inhibition by forskolin of leptin-mediated cell migration is accompanied by a strong decrease of β3 integrin subunit and FAK protein levels (Naviglio et al., 2010; Spina et al., 2013; Naviglio et al., 2009; Spina et al., 2012). Overall, our above findings provide initial evidence of forskolin as a simple natural agent able to neutralize leptin-induced oncogenic effects in breast cancer cells and extend the evidence for the potential efficacy of cAMP elevation in breast cancer therapy.
Based on their tumor-initiating ability and their elevated chemotherapy resistance, tumor-initiating cells (TICs) are considered relevant targets for cancer therapy. The strict link between the epithelial-to-mesenchymal transition (EMT) program and the TIC state is largely known and represents an attractive opportunity for drug development using agents that preferentially target more mesenchymal carcinoma cells, rather than their epithelial counterparts, in an effort to eliminate TICs (Ye et al., 2015) . Remarkably, in a current elegant study it has been shown that compounds that activate adenylate cyclase, including forskolin, act as key inducers of the epithelial non-stemlike state via a PKA dependent mechanism. The authors found that forskolin caused the mesenchymal cells to differentiate into benign epithelial derivatives that had lost their ability to effectively initiate tumors and made them more vulnerable to conventional cytotoxic treatments (Pattabiraman et al., 2016).
The tumor suppressor protein phosphatase 2A (PP2A) is frequently inactivated in human cancer and phosphorylation of its catalytic subunit (p-PP2A-C) at tyrosine-307 (Y307) has been described to inhibit this phosphatase (Mumby, 2007). Very interestingly, there is evidence that forskolin treatment dephosphorylates and increases PP2A activity in cancer cells resulting in antitumor effects, dependent on PP2A activation, including additive effects with conventional antineoplastic drugs (Perrotti and Neviani, 2013; Cristóbal et al., 2014; Cristóbal et al., 2015). Moreover, in a recent study, the effects of forskolin in combination with clinically relevant therapeutic agents were investigated in multiple myeloma (MM) cell lines as well as in primary MM cells from patients. Importantly, it has been shown that forskolin together with most of the agents tested had an additive effect on cell death. Notably, the authors propose forskolin as an adjuvant in combination with current MM therapeutic agents, especially dexamethasone, to reduce their side effects and increase their efficiency (Follin-Arbelet et al., 2015).

CONCLUSION

Notably, the burden of cancer is growing and becoming a major financial issue. The number of cancer patients and the cost of their treatment are constantly increasing. Thus, the charge of anticancer therapies in the developed world is spiralling and its economic impact is increasingly becoming more relevant for National Health Services. Efficacious and cheaper anticancer strategies compatible with a public National Health System are strongly warranted.
In general, combination chemotherapy is receiving particular attention in order to find compounds that could increase the therapeutic index of conventional antineoplastic drugs while limiting their potential toxicity.

At this regard, naturally occurring molecules with antitumor activity and with the least toxicity to normal tissues are proposed as intriguing candidates to be investigated for their possible synergistic efficacy in combination with commonly used anticancer drugs. In addition, the concept of cancer chemoprevention by natural compounds is increasingly gaining attention.
By this review, the cAMP elevating agent forskolin, among the natural compounds from medicinal plants, can be proposed as one of the most interesting molecules to possibly use in cancer therapy. Notably, the natural compound forskolin has been used for centuries in traditional medicine, is considered affordable and its safety has also been documented recently in modern medicine. However, forskolin has not been yet proven to be an effective anticancer agent in human.
More exhaustive clinical studies are needed to support this potential by forskolin. By the way, based on the evidence described in this review, our opinion is that future clinical research along such line might be strongly encouraged.

CONFLICTS OF INTEREST Authors declare no conflicts of interest.

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FIGURE LEGENDS

Figure 1. Chemical structure of forskolin from Coleus forskohlii Figure 2. Simplified scheme on cAMP homeostasis by forskolin.

Figure 1

Figure 2