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Review
. 2023 Feb 13;19(4):1241-1265.
doi: 10.7150/ijbs.80590. eCollection 2023.

Curcumin and its Analogs and Carriers: Potential Therapeutic Strategies for Human Osteosarcoma

Ko-Hsiu Lu  1   2 , Peace Wun-Ang Lu  3 , Eric Wun-Hao Lu  4 , Chiao-Wen Lin  5 , Shun-Fa Yang  6   7
Affiliations
Review

Curcumin and its Analogs and Carriers: Potential Therapeutic Strategies for Human Osteosarcoma

Ko-Hsiu Lu et al. Int J Biol Sci. .

Abstract

Curcumin is a natural polyphenol phytochemical derived from turmeric with antioxidant, anti-inflammatory, and anticancer properties but is concerned about poor solubility in water, absorption, and metabolic stability. Potent metastatic osteosarcoma is the most common primary bone cancer in children, adolescents, and young adults. It is responsible for low survival rates because of its high rate of metastasis to the lungs. To improve poor bioavailability, numerous curcumin analogs were developed to possess anticancer characteristics through a variety of biological pathways involved in cytotoxicity, proliferation, autophagy, sensitizing chemotherapy, and metastases. This review provides an overview of their various pharmacological functions, molecular mechanisms, and therapeutic potential as a remedy for human osteosarcoma. To enhance therapeutic efficacy, several liposomal nanoparticles, nanocarriers, multifunctional micelles, and three-dimensional printed scaffolds have also been developed for the controlled delivery of curcumin targeting human osteosarcoma cells. Consequently, curcumin and several potential analogs and delivery formulations are optimistic candidates to improve the currently available strategy for human osteosarcoma. However, further insight into the mechanism of action of promising curcumin analogs and the development of carriers in clinical trials of osteosarcoma needs to be investigated to improve their overall potency and clinical utility, in particular the anti-metastatic effect.

Keywords: Bioavailability; carrier; curcumin analogs; human osteosarcoma; therapeutic efficacy.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
A summary of the chemical structures of curcumin and its natural (demethoxycurcumin and bisdemethoxycurcumin) and current synthetic analogues (2c ,2f , 3c ,3f , 4c, 4f, FLLL32, EF-24, CH-5, DK1, CLEFMA, cur C086, L48H37, GO-Y078, and HO-3867) developed to overcome the limitations of curcumin and its involvement in the molecular impact on human osteosarcoma cells.
Figure 2
Figure 2
Diagram of the absorption, metabolism, circulation, and excretion of curcumin in the body. Due to its poor absorption from the gastrointestinal tract, approximately 75% of the oral intake of curcumin is excreted through the stool passage and negligible amounts are found in the urine. In the intestinal tract and during its first passage through the liver, curcumin is conjugated differently to the glucuronide and sulfate of curcumin in the intestinal tract and liver. Curcumin with or without conjugation is also reduced to dihydrocurcumin (DHC), tetrahydrocurcumin (THC), and hexahydrocurcumin (HHC), and ultimately catalyzed reduction to octahydrocurcumin (OHC), which is alternatively called hexahydrocurcuminol. After first-pass and circulation metabolism, the biliary metabolites are the main glucuronides of THC and HHC and the minor dihydroferulic acid with traces of ferulic acid. Not through intestinal absorption, intraperitoneal (i.p.) injection of curcumin partially subjects to hepatic first-pass elimination, while intravenous (i.v.) injections are directly transported into the circulation.
Figure 3
Figure 3
Schematic representation of various signaling pathways involved in the effects of curcumin on cytotoxicity, antiproliferation, cell cycle arrest, and antimetastasis in human osteosarcoma cells. The dotted line means that the pathway is controversial because the antimetastatic effect could be induced by the cytotoxic concentrations in the same study. ALP: alkaline phosphatase; Bad: B cell leukemia/lymphoma-2 (Bcl-2)-associated agonist of cell death; Bak: Bcl-2 antagonist killer 1; Bax: Bcl-2-associated X protein; Bcl-2: B cell leukemia-2; Cyt C: cytochrome c; ERR: estrogen-related receptor; H3K18Ac: acetylation of H3K18, a post-translational modification of core histone; ITPR1: inositol 1,4,5‑triphosphate receptor type 1; JAK: Janus kinase; JNK: c-Jun N-terminal kinase; miR: microRNA; MM: mitochondrial membrane; MMP: matrix metalloproteinase; NMP: nuclear matrix protein; PARP: poly(adenosine diphosphate-ribosyl)polymerase; P-gp: P-glycoprotein; RECK: reversion-inducing cysteine-rich protein with Kazal motifs; ROS: reactive oxygen species; siRNA: small-interfering RNA; STAT3: signal transducer and activator of transcription 3; Tcf: T-cell factor; and MG-63 WT, MG-63 M8, U2OS, Saos-2, LM5, Hu09 WT, Hu09 m132, HOS, and SJSA: human osteosarcoma cell lines.
Figure 4
Figure 4
Schematic representation of various signaling pathways involved in apoptosis, ferropoptosis, antigrowth, and antimetastasis effects of curcumin analogs in human osteosarcoma cells. The dotted line means that the pathway is controversial because of its cytotoxic effect induced by the same concentration. Cur: curcumin; HO-1: heme oxygenase-1; JAK: Janus kinase; JNK: c-Jun N-terminal kinase; MMP: matrix metalloproteinase; NF-κB: nuclear factor κ-light-chain enhancer of activated B cell; PI3K: phosphoinositide 3-kinase; VEGF: vascular endothelial growth factor; STAT3: signal transducer and activator of transcription 3; Tcf; T-cell factor; uPA: urokinase plasminogen activator; CH-5, CLEFMA, cur C086, DK1, EF-24, FLLL32, GO-Y078, HO-3867, L48H37, 2c, 2f, 3c, 3f, 4c, and 4f: curcumin analogs; and U2OS, SJSA, Saos-2, 143.98.2, HOS, MG-63, and 143B: human osteosarcoma cell lines.
Figure 5
Figure 5
Current curcumin analogs and carriers to target human osteosarcoma. ALN-HA-C18: alendronate-hyaluronan-octadecanoic acid; APNP: amphiphilic nanoparticle; CA: carbonated apatite; CNPs-SF/HAMA: chitosan nanoparticles encapsulated silk fibroin/hyaluronic acid esterified by methacrylate; CD: cyclodextrin; C6: C6 ceramide; HA: hyaluronic acid; HPγCD: 2-hydroxypropyl-γ-cyclodextrin; i.v.: intravenous; NP: nanoparticle; pCD: cyclodexin-based polymer; pDA: polydopamine; PLGA: poly(D,L-lactide-co-glycolic acid); SF-pDA: silk fibroin composite coated by polydopamine; SLCP: solid lipid curcumin particle; SPION@OA-F127/F68: superparamagnetic iron oxide nanoparticle coated by a 3-block copolymer Pluronic F127 and F68 on the oleic acid; Ti: titanium; TiO2: titanium dioxide; Vit: vitamin; 3D: three-dimensional; CH-5, CLEFMA, cur C086, DK1, EF-24, FLLL32, GO-Y078, HO-3867, L48H37, 2c, 2f, 3c, 3f, 4c, and 4f: curcumin analogs.
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