The Natural cAMP Elevating Compound Forskolin in Cancer Therapy: Is It Time?

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. J. Cell. Physiol. 232: 922-927, 2017. © 2016 Wiley Periodicals, Inc.

Role of cAMP and phosphodiesterase signaling in liver health and disease

“…A number of cAMP agonists and derivatives, as well as adenylate cyclase activators and analogs of PKA and EPAC, have been investigated in multiple disorders. For instance, the naturally occurring adenylate cyclase activator, forskolin, has been proposed as a dietary supplement for obesity as well as a potential drug candidate for cancer therapy [120, 121]. Forskolin has also undergone clinical trials for asthma, has been administered to patients for the treatment of glaucoma, and has been studied for its therapeutic potential role in cardiac and liver fibrosis [122–125].…”

Protein kinase A activation by the anti-cancer drugs ABT-737 and thymoquinone is caspase-3-dependent and correlates with platelet inhibition and apoptosis

“…This is especially important given that activation of cyclic nucleotide signalling in combination chemotherapy is an emerging strategy in cancer treatment. 39, 40, 41 However, PKA/PKG-activation did not block caspase-3-dependent platelet apoptosis induced by the compounds (Figures 3b and c). In contrast, both substances induced PKA activation themselves and PKA activation (Figure 4) correlated with platelet inhibition and apoptosis (Figure 5).…”

Elevated intracellular cAMP concentration mediates growth suppression in glioma cells

“…Importantly, lower cAMP levels are observed in brain tumour tissue (25.8 pmoles/mg) compared to normal healthy tissue (98.8 pmoles/mg) (Furman and Shulman 1977). Indeed forskolin, an AC activator that elevates cAMP levels, has shown promising results in ameliorating cancer development (Sapio et al 2017, Illiano et al 2018. While high levels of intracellular cAMP may kill cancer cells, exact molecular mechanisms have not been clearly elucidated.…”