Curcumin's Beneficial Effects on Neuroblastoma: Mechanisms, Challenges, and Potential Solutions

Abstract

Curcumin, a natural polyphenolic compound derived from the South Asian turmeric plant (Curcuma longa), has well-characterized antioxidant, anti-inflammatory, anti-protein-aggregate, and anticancer properties. Neuroblastoma (NB) is a cancer of the nervous system that arises primarily in pediatric patients. In order to reduce the multiple disadvantages and side effects of conventional oncologic modalities and to potentially overcome cancer drug resistance, natural substances such as curcumin are examined as complementary and supportive therapies against NB. In NB cell lines, curcumin by itself promotes apoptosis and cell cycle arrest through the suppression of serine-threonine kinase Akt and nuclear factor kappa of activated B-cells (NF-κB) signaling, induction of mitochondrial dysfunction, and upregulation of p53 and caspase signaling. While curcumin demonstrates anti-NB efficacy in vitro, cross-validation between NB cell types is currently lacking for many of its specific mechanistic activities. Furthermore, curcumin's low bioavailability by oral administration, poor absorption, and relative insolubility in water pose challenges to its clinical introduction. Numerous curcumin formulations, including nanoparticles, nanocarriers, and microemulsions, have been developed, with these having some success in the treatment of NB. In the future, standardization and further basic and preclinical trials will be required to ensure the safety of curcumin formulations. While the administration of curcumin is clinically safe even at high doses, clinical trials are necessary to substantiate the practical efficacy of curcumin in the prevention and treatment of NB.

Keywords: apoptosis; cancer prevention; curcumin; natural substances; neuroblastoma; oncology.

Figure 1

Chemical structure of curcumin, a polyphenolic chemical constituent of turmeric with antioxidant, anti-inflammatory, and anticancer effects. Curcumin is a beta-diketone compound containing two substituted aromatic rings linked by a seven-carbon chain. Each aromatic ring has one hydroxy and one methoxy group.

Figure 2

Curcumin, as a multitarget compound, induces apoptosis and cell cycle arrest in neuroblastoma (NB) cells through the modulation of PTEN–Akt, NF-κB, and p53 signaling; mitochondrial dysfunction; and caspase activation. (A) Intracellular signaling mechanisms within NB cells favor proliferation. The proliferative Akt, NF-κB, and ERK 1/2 pathways, as well as the antiapoptotic Bcl-2 and Survivin proteins, are active and upregulated. Apoptotic signals via mitochondrial dysfunction, cytochrome c release, p53, and caspases are downregulated. Cyclin-dependent kinase inhibitors (p21 and p27) are inactive, allowing for cell cycle progression. (B) Curcumin modulates intracellular signaling in NB cells in favor of apoptosis and cell cycle arrest. Curcumin upregulates PTEN, which in turn downregulates Akt and NF-κB and upregulates FOXO3a and Fas pathway signaling. Moreover, curcumin-induced ROS generation elevates intracellular ROS levels and supports both FOXO3a and p53_n signaling. Together, p53_n, Fas pathway, and Akt signaling, along with mitochondrial membrane potential (MMP) depolarization, promote the release of cytochrome c from the mitochondria into the cytosol, where it supports caspase activation. Mitochondrial dysfunction also involves the downregulation of Hsp60, which ultimately leads to the downregulation of Survivin—a protein that ordinarily inhibits caspase activity. Caspase 3 cleaves PARP-1, causing apoptosis, while FOXO3a and p53 activate cyclin-dependent kinase inhibitors, which induce cell cycle arrest.

Figure 3

Oncologic signaling pathways are shared by curcumin and the anti-NB cancer drugs doxorubicin and cisplatin. Curcumin, doxorubicin, and cisplatin induce mitochondrial dysfunction through the upregulation of Bax and downregulation of Bcl-2. While curcumin also induces the Fas signaling pathway, doxorubicin does not, since it does not upregulate the ligand needed by the signaling pathway to proceed (Fas-L). Ultimately, the pathways lead to the activation of caspases and apoptosis.