Chalcone Scaffold in Anticancer Armamentarium: A Molecular Insight

Abstract

Cancer is an inevitable matter of concern in the medicinal chemistry era. Chalcone is the well exploited scaffold in the anticancer domain. The molecular mechanism of chalcone at cellular level was explored in past decades. This mini review provides the most recent updates on anticancer potential of chalcones.

Figure 1

Chemical structure of chalcone.

Figure 2

Action of chalcone on cell cycle.

Figure 3

Chalcones against leukemia cell lines. (1) CC₅₀ of 30 μM, (2) CC₅₀ of 40 μM, and (3) CC₅₀ of 40 μM: increases proapoptotic proteins Bax, Bid, and Bak (only chalcone 2) and decreases antiapoptotic Bcl-2 expression. Caspase-9 and caspase-12 activation increases CHOP expression resulting in induction of ER stress. (4) IC₅₀ values (4 to 8 μM) and (5) IC₅₀ values (4 to 8 μM): induction of apoptosis through the reduction of the mitochondrial membrane potential, reduction in Bcl-2 expression, increase in Bax expression, and increase in active caspase-3. ((6a) to (6c)) IC_50s between 12 and 85 μM for HDAC isoenzymes, inhibiting total HDAC activity by 20–50% at 100 μM: histone deacetylases (HDACs) inhibitor. (7) IC₅₀ of 13.7 ± 0.8 μM: caspase-3 and caspase-7 activation.

Figure 4

Chalcones against colon cancer cell lines. (8) IC₅₀ of 14.5 ± 1.1 μM: increases proapoptotic proteins Bax, Bid, and Bak (only chalcone 2) and decreases antiapoptotic Bcl-2 expression. Caspase 9 and caspase 12 activation increases CHOP expression resulting in induction of ER stress. (9) IC₅₀ of 4.39 μM: increases the death receptors expression (TRAIL-R1 and TRAIL-R2) (Tumor necrosis factor- (TNF-) related apoptosis-inducing ligand) and proapoptotic markers (p21, Bad, Bim, Bid, Bax, Smac, caspase-3, and caspase-8) as well as reducing the antiapoptotic markers (livin, XIAP, and HSP27).

Figure 5

Chalcones against cervix adenocarcinoma cell lines. ((10a) to (10c)) IC₅₀ values ranging from 2.36 to 2.73 μM: increases p18 Bax, accumulation of cells in S, and G₂/M phases. (11) IC₅₀ of 4.7 to 7.6 μM: induction of caspase-dependent intrinsic pathway p53 and its transcriptional target PUMA upregulation.

Figure 6

Chalcones against lung cancer and breast cancer cell lines. (12a) IC₅₀ values of 1.35–2.07 μM and (12b) IC₅₀ values of 7.27–11.07 μM: upregulation of the DR5; extrinsic pathway of apoptosis. ((13a) to (13d)) IC₅₀ values ranging from 1.76 to 6.11 μM: inhibited tubulogenesis, caspase-3 and caspase-8 activation, and inhibitory potential against matrix metalloproteinases (MMP-2) secretion. (14) IC₅₀ values of 1.41 and 0.70 μM: cell cycle arrest at G₂/M phase, activation of caspase-3, and cleavage of PARP. (15) IC₅₀ value of less than 0.10 μM: cell cycle arrest at G₂/M phase, activation of caspase-3, and cleavage of PARP. (16) IC₅₀ of 0.8 μM: enhances tubulin polymerization suggesting the activity as microtubule stabilizing agents. (17) IC₅₀ of 0.16 to 0.44 μM and (18) IC₅₀ of 0.56 to 0.65 μM: suppress the activation of NF-κB pathway. (19a) IC₅₀ of 2.25 μM and (19b) IC₅₀ of 3.29 μM: induced DNA fragmentation and apoptosis.

Figure 7

Chalcones against hepatocellular carcinoma cell lines. (20) IC₅₀ of 6.25  μM: mitochondria dependent pathway involving inhibition of Bcl-2 expression leading to disintegration of the outer mitochondrial membrane. Caspase-3 and caspase-9 activities. (21) IC₅₀ of 10 μM: hypoxia inducible factor-1 (HIF-1) inhibitor.

Figure 8

Chalcones against bladder and prostate cancer cell lines. (22) Concentration of 6 μg/mL: reduction in the expression of cyclin A and cyclin B1, decrease in the expression of Cdc2 and an increase in the expression of p21 and p27, increase in the expression of proapoptotic proteins Bax and Bak, and decrease in the expression of antiapoptotic proteins Bcl-2, Bcl-xL proteins; NF-κB activation by increasing the expression of IκBα in cytoplasm leads to apoptosis. (23) IC₅₀ value of 5.95 μM: copper ions might act as penetration enhancers of chalcones into cancer cells and might act as inhibitors of drug efflux proteins.

Figure 9

Chalcones against multiple cancer cell lines. ((24a) to (24c)) GI₅₀ of 0.21 to 57.6 μM: topoisomerase-I and topoisomerase-II inhibition. (25) IC₅₀ of 0.15 to 0.52 μM: arrest cells in the G₂/M phase of the cell cycle and inhibit the polymerization of tubulin. Binds into the colchicine binding site of tubulin (molecular docking study). (26) IC₅₀ values of 0.22 to 1.80 μM: induced cell cycle arrest in G₂/M phase and inhibited the polymerization of tubulin; binds at the colchicine binding site of tubulin (from molecular docking analysis). (27) IC₅₀ value of 0.89 μmol/L: cell division cycle 25 (CDC25) inhibitor. (28) IC₅₀ values of 1.76 μmol/L: cell division cycle 25 (CDC25) inhibitor. (29) IC₅₀ value of 0.01 μg/mL and 0.04 μg/mL: molecular mechanism not studied. (30) IC₅₀ values of 6.4 μM and 8.5 μM: cytotoxic, molecular mechanism not studied. (31a) IC₅₀ value of 1.02 μM and 0.79 μM and (31b) IC₅₀ value of 0.81 μM and 1 μM: cytotoxic.

Figure 10

Chalcones against multiple cancer cell lines. (32) IC₅₀ = 0.53 μM and (33) IC₅₀ value of 8.18 μM: could snugly occupy the colchicine binding site of β-tubulin (molecular docking study). (34) Concentration of 0.2 μM: cell cycle arrest in G₂/M phase promoted tubulin polymerization into microtubules and caused microtubule stabilization similar to paclitaxel. (35) IC₅₀ values of 1.60 μM and (36) IC₅₀ values of 2.82 μM: inhibition of clonogenicity.

Figure 11

Chalcone obtained by using a fission yeast bioassay. (37) Concentration of 8 μM to 20 μM induces DNA damage which blocks cell cycle progression at the G₂/M transition in a Rad3-dependent and Chk1-dependent manner.

Figure 12

Chalcone against cathepsin B and cathepsin H obtained from goat liver. (38) K _i values of 6.18 × 10⁻⁸ M for cathepsin B. K _i values of 2.8 × 10⁻⁷ M for cathepsin H: cathepsin B and cathepsin H inhibitor.

Figure 13

Chalcones against brain cancer cell line. ((39a) and (39b)) cotreatment of 10 μM with TRAIL (25 ng/mL): TRAIL sensitizers.

Figure 14

Chalcone against multidrug resistant cancer cell lines. (40) IC₅₀ value of 2.54 μM: arresting the cell cycle between G₀/G₁ phases, which is via the strong induction of apoptosis by disrupting mitochondrial membrane potential (MMP) and an increased production of reactive oxygen species (ROS). (41) Combined effects of 36 and Tipifarnib reduce the IC₅₀ value of Tipifarnib from 9.0 μM (applied alone) to 3.8 μM: increased the expression of HIF-1α. (42) GI₅₀ of 3.87 μM and (43) GI₅₀ of 3.95 μM: trigger cell cycle arrest at the G₂/M phase and apoptotic cell death, aurora A kinase inhibitor.