The drug molecules with coumarin and its derivatives as the basic skeleton have a wide range of biological activities, such as antioxidant, anticoagulant, antiviral, antibacterial, anti-inflammatory, hypoglycemic, anticancer and neuroprotective, which makes coumarins attractive for further optimization as novel drug templates. So far, there are more than 35 clinical stage and marketed drugs containing coumarin.
Coumarin targets multiple cancer signaling pathways such as kinase inhibition, cell cycle arrest, angiogenesis inhibition, heat shock protein (HSP90) inhibition, telomerase inhibition, antimitotic activity, carbonic anhydrase inhibition, monocarboxylic acid transport protein inhibition, aromatase inhibition and sulfatase inhibition. Next, we will introduce the detailed information of coumarin acting on cancer signaling pathways.
Kinase Inhibitors
Kinases are enzymes that catalyze the transfer of phosphate groups to target proteins. They play key roles in regulating countless growth factor signaling. The activated form of the kinase can lead to increased cell proliferation, prevent apoptosis, and promote angiogenesis and metastasis. Activated forms of kinases can lead to increased cell proliferation, prevent apoptosis, and promote angiogenesis and metastasis, while somatic mutations that activate kinases are fundamental mechanisms of tumorigenesis. Since all of these effects are triggered by kinase activation, they are key targets for inhibition by coumarins and their derivatives. In 2014, Nasr et al. synthesized and evaluated the anticancer activity of coumarin derivatives against drug-resistant pancreatic cells and drug-sensitive cell lines such as Hep-G2 and CCRF. The coumarin derivatives were found to be more effective than the reference drug doxorubicin. It was observed that coumarin hydrazide-hydrazone pharmacophores showed better activity than compounds with coumarin or hydrazide-hydrazone pharmacophores.
Cell Cycle Arrest
Coumarin has been reported to block various phases of the cell cycle, such as G0, G1, S, and M phases, ultimately leading to apoptosis. They were found to induce apoptosis through cysteine aspartase-dependent intrinsic pathways and changes in cellular levels of Bcl-2 family proteins. In 2013, Kumar et al. synthesized 3-(4,5-dihydro-1-phenyl-5-substituted phenyl-1H-pyrazol-3-yl)-2H-chromium-2-one derivatives and evaluated their anticancer activity against 60 cancer cell lines. It has been observed that the 8-lactone ring of the coumarin nucleus is the basis for its significant anticancer activity, which is caused by inducing G1 arrest of the cell cycle.
Angiogenesis Inhibitors
Angiogenesis is also a primary target of coumarin derivatives. They have been found to inhibit angiogenesis by inhibiting fibroblast growth factor-2 (FGF-2)-mediated proliferation, migration and tubule formation. In addition, coumarin derivatives can reduce the expression of vascular endothelial growth factor (VEGF) mRNA levels through phosphorylation of nuclear factor kB (NF-kB) and IKKa. Interestingly, the phosphatidylinositol 3-kinase (PI-3K)/Akt signaling pathway was not affected.
HSP90 Inhibitors
Extensive experiments have shown that coumarin can directly bind to the up-regulated HSP90 in various cancers. At the same time, various client proteins may also cause normal cells to transform into cancer cells. Coumarin leads to the ultimate antiproliferative effect by degrading co-chaperone and client proteins. Coumarin-like compounds have been reported to cause depletion of key regulatory HSP90-dependent kinases in vitro and in vivo, including Src, Raf-1, and ErBB2 proteins encoded by the ErBB2 gene.
Telomerase Inhibitor
Telomerase is an enzyme that helps maintain telomere length in human stem and cancer cells by adding TTAGGG repeats to telomeres. Telomerase activity was found only in tumor cells but not in adjacent normal cells. Different inhibitors including coumarin are thought to inhibit telomerase. Wu et al. prepared novel coumarin derivatives as potential telomerase inhibitors and found that some coumarin compounds had high antiproliferative and telomerase inhibitory activities against various cell lines.
Antimitotic Agents
Mitosis is a cell cycle process that occurs in both normal cells and cancer cells, by which chromosomes are segregated into two identical sets of chromosomes. Coumarin derivatives inhibit cell division by directly acting on mitotic phase mainly including prometaphase and metaphase, thereby inspiring these derivatives to target tubulin. In 2013, Tsyganov et al. developed antimitotic compounds with coumarin structures.
Carbonic Anhydrase Inhibitors
Carbonic anhydrase (CA) is controlled by hypoxia-inducible transcription factor (HIF) and is an intrinsic marker of hypoxia in many cancers. Its expression is closely related to different types of cancer hypoxic cells. Carbonic anhydrase significantly catalyzes the hydration of carbon dioxide to bicarbonate and protons, promoting acidification of the tumor environment, leading to the acquisition of a metastatic phenotype and resistance to several anticancer drugs. It has been reported that coumarins can control the pH balance of tumor cells and inhibit the activity of tumor-associated bicarbonases in the treatment of hypoxic tumors.
Monocarboxylate Transporters (MCT) Inhibitors
Coumarin was found to block lactic acid uptake. Under hypoxic conditions, cancer cells consume glucose and release lactate at a higher rate, which is recaptured by oxygenated cancer cells to promote TCA cycling and promote tumor growth. Monocarboxylate transporters (MCTs) are the major lactate transporters. MCT1 and MCT4 are significantly expressed in cancer cells. MCT1 has been found to show a better affinity for lactate, which allows lactate to enter oxidative tumor cells. In contrast, MCT4 shows low affinity but higher turnover and is expressed in glycolytic tumor cells as well as in lactate-exporting tumor-associated fibroblasts. Thus, blockade of MCTs by coumarin prevents the utilization of lactate by oxygenated tumor cells and forces them to become dependent on glucose. Thus, hypoxic tumor cells that are rely on glucose for replacement die due to glucose deprivation.
Aromatase/ Sulfatase Inhibitors
Coumarin derivatives are also able to modulate several cancer-specific enzymes, such as aromatase and sulfatase. Steroid sulfatase (STS) is responsible for converting estrone sulfate into active hormones, therefore, inhibition of these enzymes by bicyclic and tricyclic coumarates can reduce active hormones that cause breast, endometrial, and prostate cancer biosynthesis. They also inhibit aromatase to prevent the conversion of other hormones such as androgens to estrogen. Thus, inhibition of aromatase also results in the formation of genotoxic metabolites of estrogen. These metabolites include catechol estrogens, which induce mutations and inhibit other oncogenic metabolites such as 2-hydroxyestradiol and 4-hydroxyestradiol.
