Anticancer Potential of Furanocoumarins: Mechanistic and Therapeutic Aspects

Cancer is one of the most extreme medical conditions in both developing and developed countries around the world, causing millions of deaths each year. Chemotherapy and/or radiotherapy are key for treatment approaches, but both have numerous adverse health effects. Furthermore, the resistance of cancerous cells to anticancer medication leads to treatment failure. The rising burden of cancer overall requires novel efficacious treatment modalities. Natural medications offer feasible alternative options against malignancy in contrast to western medication. Furanocoumarins’ defensive and restorative impacts have been observed in leukemia, glioma, breast, lung, renal, liver, colon, cervical, ovarian, and prostate malignancies. Experimental findings have shown that furanocoumarins activate multiple signaling pathways, leading to apoptosis, autophagy, antioxidant, antimetastatic, and cell cycle arrest in malignant cells. Additionally, furanocoumarins have been shown to have chemo preventive and chemotherapeutic synergistic potential when used in combination with other anticancer drugs. Here, we address different pathways which are activated by furanocoumarins and their therapeutic efficacy in various tumors. Ideally, this review will trigger interest in furanocoumarins and their potential efficacy and safety as a cancer lessening agents.


Introduction
Cancer exacts one of the greatest medical tolls on humankind, requiring a proactive procedure for prevention and treatment. An enormous number of patients succumb to cancer every year. It is one of the chief reasons for mortality around the world, and the number of cases is continually expanding and estimated to reach 21 million by 2030. The lack of efficient anticancer treatments remains a clinical problem [1,2]. Chemotherapy and/or radiotherapy are the main clinical approaches to cancer treatment, yet both have documented adverse effects [3][4][5][6]. Cancer treatment affects not only rapidly multiplying cancerous cells but also normal body cells (bone marrow, gastrointestinal tract (GIT), and hair follicles); therefore, these treatments may give rise to severe adverse symptoms. Moreover, quick disposal and

Chemistry of Furocoumarins
The exact molecular mechanism of such an activity relies upon the chemical structure of furanocoumarins, which depends on the furan ring and coumarin backbone combination in an angular or linear structure just as the type, location, and the number of the substituents attached [11]. The CH3 presence at C5 improves the tumor properties of psoralen and 5-MOP, paying little heed to the substituent location. The substitution of the methoxy group with an isopentenyloxy moiety in the C5 position prompted abatement in the pro-apoptotic properties of the compound [20][21][22]. Angelicin is the most straightforward angular furanocoumarin and it displays counter cancer properties. Analogous to linear furocoumarins, angular analogs can be substituted with a methoxy or isopentenyloxy group. Methoxy subordinates of angelicin incorporate isobergapten and sphondin. Isobergapten, for example, 5-methoxyangelicine, is a linear isomer of bergapten with a methoxy group joined to the fifth (C5) carbon atom. Thus, sphondin (6-methoxyangelicin) can be considered as an angular analogue of xanthotoxin. The thing that matters is, be that as it may, that the methoxy group is appended to the C6 position in 6-methoxyangelicin and to the C8 atom in the 8-MOP [11].

Bioavailability of Furocoumarins
Furanocoumarins are rapidly absorbed from food into the human bloodstream and detected in plasma within 2-15 min after administration [20], and distributed to the skin, blood, liver, brain, spleen, kidney, and testis. In plasma, furanocoumarins bind to albumins and other plasma proteins. Furanocoumarins are metabolized to psoralen and isopsoralen by intestinal bacteria in the digestive tract. Then, furanocoumarins are excreted into urine as hydroxylated or glucuronated products within 1 h after ingestion. They remain in urine as long as 24 h post-administration. It was also observed that furanocoumarins are converted to bergaptol before excretion [11,21,22]. A significant advance in the investigation of the anticancer properties of furanocoumarins was the revelation of their antiproliferative activity arresting cell-cycle capture and causing cell death [23][24][25]. At the cellular levels, furanocoumarins appear to affect actin filaments, which might be valuable in metastasis prevention [26].
The antitumor effects of angelicin involves decreased expression of p-VEGFR2 and PI3K/Akt signaling inhibition in HepG2 and Huh-7 cells. In the same study, angelicin was shown to decrease p-VEGFR in mouse liver orthotopic xenograft model [17]. Bergamottin suppresses TGF-β initiated EMT and the cell invasive potential by PI3K, Akt, and mTOR kinases [35].
Psoralen causes exosomes formation and secretion reduction through p53 and PPAR activation in MCF-7/ADR cells, which showed its role against chemotherapy resistance in breast cancer [83].

Role in MDR Cancers
Cancer cell defiance to chemotherapy is one of the significant deterrents for counter cancer medications due to the involvement of different mechanisms. The main causes are related to the increment of multidrug efflux pumps, including P-gp by tumor cells, and showed MDR. Coumarins have a significant role in MDR inversion [106][107][108].
Exosomes, secreted from tumor cells to promote tumor progression, such as metastasis and MDR, activate sequestration of anticancer drugs by MDR-1 and P-gp [116]. Psoralen significantly reduces the number of exosomes, which correlates with increased MCF-7/ADR cells' sensitivity for apoptosis under the influence of chemotherapy. Similar observations were seen in A 549/D16 lung cancer cell lines [11,83,117].

Conclusions
Chemotherapy and radiation are the staples for treatment of malignant growth, however, both have serious adverse health symptoms. It is known that tumors have developed many mechanisms at the molecular level enabling cell survival during chemotherapy. Therefore, it is essential to develop novel pharmaceuticals with increased efficacy and reduced toxicity. This review highlights the potential for furanocoumarins to be clinically beneficial in cancer, particularly given their specificity to tumor cells (while sparing normal cells). In vitro investigations have shown that furanocoumarins affect a range of cellular mechanisms, such as apoptosis, autophagy, and cell cycle arrest. ER stress induction mainly caused by NF-κB inactivation, PI3K/Akt inhibition, and p53 modulation. Furanocoumarins are also effective in different MDR cancers that are the main cause of anticancer therapeutics failure. Compounds in this class have also have been shown to positively synergize with commonly used anticancer drugs. The fast absorption of furanocoumarins from food into the human bloodstream is also noteworthy [134]. Furanocoumarins, by inhibiting CYP P450 3A4, not only have anticancer properties but also when co-administered with a low bioavailability anticancer compound can increase oral bioavailability [135]. Thus, as to improve genuine treatments for various sorts of tumors, nanomedicine has developed new strategies coordinated to build the efficacy of medications focusing on tumors and limit their side effects [136,137]. Furanocoumarin-loaded lipid-polymer-hybrid-nanoparticles represent an additional option for sustained release of these molecules to improve efficacy and synergistic effects with other anticancer agents and against MDR cancers [108,138,139]. To date, most focus has been on in vitro studies, making it hard to reach solid conclusions on the efficacy of furanocoumarins in vivo. Nonetheless, studies aimed at characterizing furanocoumarin's efficacy in vivo as well as clinical studies are encouraging, supporting the need for future studies to better characterize furanocoumarin's potential as efficacious anticancer treatment modalities.