A kojic acid derivative promotes intrinsic apoptotic pathway of hepatocellular carcinoma cells without incurring drug resistance

Abstract

Hepatocellular carcinoma is one of the most pervasive cancers with low prognosis, high frequency of recurrence, and metastasis. Studies conducted have focused on extricating novel strategies for successful treatment. Kojic acid and its derivatives are already proven to have depigmenting, anti‐inflammatory, and anti‐neoplastic properties. In the present study, kojic acid and its 10 distinct derivatives were tested on HEPG2 cell line for their possible anti‐cancer effect and seven of them were observed to be cytotoxic. Compound 6 was chosen to proceed as the IC50 dosage for HEPG2 cells was lower in comparison with the other derivatives and kojic acid itself. Further experiments pointed out that intrinsic apoptotic pathway was triggered with the exposure of the cells to IC50 concentration of the derivative as the treatment led to escalation of intracellular ROS, induction of TP53 gene, and activation of caspase 3/7. Pro‐apoptotic Jnk and Bax genes were not triggered suggesting that the apoptotic pathway advance through an alternative route. Complementary experiments are in need; howbeit, the current findings suggest that the derivative offers a novel promising approach against hepatocellular carcinoma as it is not detrimental to healthy cells within the concentrations applied, and it does not induce drug resistance.

Biological activities and safety data of kojic acid and its derivatives: A review

“…Non-cancerous cell lines, such as HGF-1 human gingival fibroblasts and MRC-5 human lung cell lines, can be employed. 16,17,68 The antitumor studies evaluated in this review demonstrated toxic effects of kojic acid derivatives for cancerous cell lines and safe concentrations for normal cell lines in cell viability assays with IC50 determinations, indicating the studied kojic acid derivatives as safe molecules in such conditions.…”

“…For HEPG2 hepatocellular carcinoma cell line, kojic acid derivatives trigger an intrinsic p53 apoptotic pathway by increasing intracellular ROS concentration. The derivatives led to mitochondrial events which caused activation of caspase 3/7, hence apoptosis 68. Antitumor activity of metal complexes of kojic acid was tested on VC-8-BRCA & VC-8, (ovarian cancer cell lines).…”

Anticancer Activity of Mannich Bases: A Review of Recent Literature

“…carcinoma cells, and the use of the piperidine Mannich bases in investigating its mechanism of action showed that it triggered apoptosis by increasing the levels of intracellular ROS, induction of TP53 gene, and activation of caspase 3/7 [65] . In another series of Mannich bases of allomaltol, compound 51 (R =H, R 1 =3,4‐Cl 2 ) (Figure 7) was found to be the most potent against MCF‐7 cells (IC 50 = 97 μM) and also against MDA‐MB‐231 (IC 50 = 48 μM), and investigation of its mechanism of action demonstrated that apoptosis occurred predominantly either through a p53‐dependent or through a p53‐independent mechanism, depending of the type of breast cancer cell involved [66] .…”

“…In a collection of ten bisaminomethyl derivatives of 3-hydroxypyran-4-one, two compounds 52 (R 1 = 2-F-4-Br, NR 2 = piperidin-1-yl or pyrrolidin-1-yl) (Figure 7) had IC 50 values of approximately 35 μM against HepG2 hepatocellular carcinoma cells, and the use of the piperidine Mannich bases in investigating its mechanism of action showed that it triggered apoptosis by increasing the levels of intracellular ROS, induction of TP53 gene, and activation of caspase 3/7. [65] In another series of Mannich bases of allomaltol, compound 51 (R = H, R 1 = 3,4-Cl 2 ) (Figure 7) was found to be the most potent against MCF-7 cells (IC 50 = 97 μM) and also against MDA-MB-231 (IC 50 = 48 μM), and investigation of its mechanism of action demonstrated that apoptosis occurred predominantly either through a p53-dependent or through a p53-independent mechanism, depending of the type of breast cancer cell involved. [66] The best IC 50 value of a Mannich base 53 (Figure 7) obtained from kojic acid as substrate and ciprofloxacin as amine reagent was against HCT-116 human hepatoma cell line (IC 50 = 88 μM), while the copper complex of compound 53 was more potent against HepG2 (IC 50 = 11 μM).…”

Sonochemistry in an organocatalytic domino reaction: an expedient multicomponent access to structurally functionalized dihydropyrano[3,2-b]pyrans, spiro-pyrano[3,2-b]pyrans, and spiro-indenoquinoxaline-pyranopyrans under ambient conditions

“…1 5-Hydroxy-2-(hydroxymethyl)-4 H -pyran-4-one, commonly known as kojic acid is an oxygen-containing natural γ-pyrone generated by filamentous fungi and numerous kinds of bacteria including Aspergillus , Penicillium, and Acetobacter, etc. 2 The kojic acid nucleus and its analogs have drawn immense significance in recent years due to their various application in the medicinal and pharmaceutical industry, 3 food industry, 4 cosmetic and personal care products, 5 agriculture, 6 and chemical industry. 7 By taking into consideration kojic acid's structural characteristics and broad-spectrum activities, a substantial attempt was made not just towards its synthesis but also to using them as an essential constituent for construction and identification of potent structural fragments.…”