Breast cancer is one of the major cancers with a high mortality rate in women across the world. Based on diagnostic evidence, more than 15–20 % of the total breast cancer depicted triple-negative breast cancer (TNBC) with high recurrence and worse survival rate compared to non-TNBC [1–3]. TNBC is a fatal breast cancer subtype with absence of three primary receptors, namely estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) [4–6]. This attitude is directly correlated with elevated lipolysis or fatty acid oxidation (FAO) for high energy compensation during rapid proliferation, even in hypoxic conditions [7–9]. The metastatic cancer cell undergoes metabolic rearrangements, including alterations in fatty acid transport, accumulation of lipid droplets, de novo lipogenesis and β-oxidation to achieve extensive ATP demand [10, 11]. It has been hypothesized that glycolysis solely plays a significant role in cancer progression. Later, the fact was at stake since the discovery of direct mitochondrial relation with fleeting cancer progression [12, 13]. The mitochondrial bioenergetics and FAO association have been witnessed to stage an imperative role in cancer stemness, survival, proliferation and chemoresistance [14, 15].
Carnitine palmitoyltransferase system acts as a pivotal mediator in cancer metabolic plasticity in active association with FAO. This system is solely responsible for long-chain fatty acid (LCFA) delivery from the cytoplasm to mitochondria for fatty acid β-oxidation, and carnitine palmitoyltransferase 1 (CPT1) catalyzes rate-limiting steps of FAO. Thereby, CPT1 and FAO targeting breast cancer have been hypothesized to be an optimistic approach towards anticancer therapeutics [16–18]. Besides, fatty acid synthase (FASN), a rate-limiting enzyme, plays a decisive role in LCFA processing in FAO. Overexpression in FASN has been considered to promote breast cancer progression, while up-regulation in acetyl-CoA carboxylase (ACC) has shown negative feedback limiting breast cancer regression [19, 20]. Interestingly, the direct involvement of different enzymes and carriers in the FAO pathway, modulating beta-oxidation in cancer cells, is of intense interest since time immemorial. Moreover, the inhibition exerted by them remains associated with antitumor activities and thereby needs quick surveillance over time.
Despite the availability of several synthetic anticancer drugs, natural drugs have gained the immense spotlight in recent times due to minimal side effects [21]. The natural phytochemicals from edible plants have shown remarkable possibilities towards effective anticancerous treatment with beneficial clinical advantages [22, 23]. Mikania micrantha Kunth (bitter vine or mile-a-minute vine), an invasive weed of the family Asteraceae, contains various bioactive compounds such as flavonoids, phenols, and polyphenols. This globally famed antiseptic and folk medicine are applied for assessment of antibacterial activities mostly and rarely were explored in cancer therapies [24, 25]. Quercetin (QT) [IUPAC name: 2-(3, 4-dihydroxyphenyl)-3, 5, 7-trihydroxy-4H-chrome-4-one; CAS number: 117-39-5 6151-25-3], a flavonol with anti-lipid oxidative property has been widely used in cancer treatment. It undergoes various activities like decreases the FASN expression, inhibits proliferation of carcinoma cells and significantly improves the plasma non-enzymatic antioxidant capacity during chemotherapy [25, 26]. It also elevates the lipid peroxides level, reduces tumor size and the cumulative number of papilloma, and acts as a potent inhibitor of lipogenesis in prostate and breast cancer cells by inhibiting FASN activity [27, 28]. Reports evidenced that QT potentially inhibit lipid synthesis by suppression of peroxisome proliferator-activated receptor-gamma (PPARγ) and CCAAT-enhancer-binding protein a (C/EBPα) and activation of AMP-activated protein kinase (AMPK) in 3T3-L1 cells [29]. Eventually, QT has been proven to modulate the activity of hepatic cholesterol and hepatic cholesterol 7α-hydroxylase, the enzyme involved in cholesterol metabolism, promoting the strategic conversion of cholesterol-to-bile acid [30]. Dietary QT is intriguingly reported to limit FAO in metastatic breast cancer to stimulate DNA damage and apoptosis [31–33]. Therefore, it will be worth exploring QT from non-dietary sources as effective anticancer therapeutics.
In this study, we have synthesized a flavonoid subtype, QT, from Mikania micrantha Kunth and evaluated its metabolism-targeted anticancer activities via checking the outcome of FAO associated rate-limiting enzyme. QT determined the fate of total intracellular glycolysis and mitochondrial oxidation rate promoting cell death and apoptosis. Additionally, overall molecular action has been successfully predicted through in silico molecular binding assay via 3D (three-dimensional) protein structure preparation of CPT1 followed by an extra-precision (XP) molecular docking, elucidating the plausible mechanistic binding interactions of QT with CPT1. Lastly, in-vivo experimentation in female BALB/c breast cancer mice model has portrayed the intracellular lipid profiling and oxidative stress management enabling antitumor activities of QT, confirming its successive metabolism-targeted anticancer activities.