Potential of Curcumin-Quercetin Loaded Nanostructured Lipid Carriers as Oral Squamous Cell Carcinoma Adjuvant Therapy by Downregulating AKT/PI3K Signaling Pathway
Alexander Patera Nugraha1,2,3, Diona Olivia Yudianto2, Amelia Aisyiah Anwar4,
Alqomariyah Eka Purnamasari4, Rifqah Ananda Mappananrang4,
Nastiti Faradilla, Ramadhani5,Muhammad Luthfi6,
Tengku Natasha Eleena Binti Tengku Ahmad Noor7, Albertus Putera Nugraha8,
Andreas Pratama Nugraha9,10
1Dental Regenerative Research Group, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia.
2Orthodontics Department, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia.
3Graduate Student of Dental Health Science, Universitas Airlangga, Surabaya, Indonesia.
4Undergraduate Student, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia.
5Dentomaxillofacial Radiology Department, Faculty of Dental Medicine,
Universitas Airlangga, Surabaya, Indonesia.
6Oral Biology Department, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia.
7Malaysian Armed Forces Dental Officer, 609 Armed Forces Dental Clinic,
Kem Semenggo, Kuching, Sarawak, Malaysia.
8Undergraduate Student, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
9Graduate Student of Clinical Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
10Oral and Maxillofacial Surgery Resident, Faculty of Dental Medicine,
Universitas Airlangga, Surabaya, Indonesia.
*Corresponding Author E-mail: alexander.patera.nugraha@fkg.unair.ac.id
ABSTRACT:
Introduction: Oral squamous cell carcinoma (OSCC) is an oral epithelial neoplasm with worldwide prevalence of 95% among all oral malignancies. Therapy of OSCC include radiation, chemotherapy, and surgery but causes subsequent cell death, ineffective long-term therapy, and infection risk at surgical site. Curcumin-quercetin is flavonoid derived from Curcuma longa and Allium cepa that can induce apoptosis and inhibit cells metastasis. Combination of curcumin-quercetin has low solubility hence encapsulated by nanoparticle is necessary. Nanostructured lipid carriers (NLCs) can enhance loading capacity and improve stability of curcumin-quercetin, biocompatible, and enhance site-specific targeting efficiency. Administration of combination of curcumin-quercetin loaded nanostructured lipid carrier by injection targeting OSCC cell. Purpose: To analyze the potency of curcumin-quercetin loaded NLCs as OSCC therapy by downregulating AKT/PI3K signaling pathway. Discussion: Curcumin-quercetin loaded NLCs are injected into the body then reach the target cells. This combination later would be encapsulated releasing curcumin-quercetin. Curcumin-quercetin suppresses the AKT/PI3K signaling pathway which is considered as strong cell cycle inductor, inhibitor of pro-apoptotic proteins expression, and has a pivotal role in OSCC metastasis. Inhibition of the pathway decreases the expression of cyclin A/D/E and manifests in the G1/G2/M phase arrest. This condition accompanied by p53 and FOXO-1 expression leads to apoptosis. Downregulating of this pathway decreases NF-kB expression then the expression of MMP-2/9 is lowered and manifests in inhibition of extracellular matrix degradation. This condition leads to migration and metastasis inhibition. Conclusion: Curcumin-quercetin loaded NLCs is potential for OSCC therapy by downregulating AKT/PI3K signalling pathway.
KEYWORDS: Herbal, Medicine, Cancer, non-communicable disease, dentistry.
INTRODUCTION:
Oral squamous cell carcinoma (OSCC) is the major type of cancer originating in the head and neck region that represents the main malignancy developed from oral mucosal epithelium. OSCC ranked as the 6th most frequent cancer with a worldwide prevalence nearly of 90-95%.1,2 OSCC is primarily associated with the chewing of areca nut, tobacco smoking, consuming of alcohol, chronic trauma, poor dental hygiene, and genetic susceptibility.1,3 The patient suffered by OSCC had significant levels of orofacial pain that can restrict the oral function and limit the patient’s physical movement. Oral cancer pain is arised from the accumulation of mediators that triggered by the cancer and associated cells leads to the activation of primary nociceptive afferent nerve. This condition will reduce the patient’s quality of life.4
There are many oral malignant disorders that potentially transform into OSCC including leukoplakia, verrucous leukoplakia, erythroleukoplakia, erythroplakia, oral submucous fibrosis (OSMF), and oral lichen planus (OLP). These clinical presentations support early detection of cancer to improve prognosis and increase the patient survival rate. Diagnosis modalities in OSCC detection can be examined by exfoliative biopsy, histopathologic analysis, cytology, and saliva biomarker. The gold standard to examine and diagnose OSCC are biopsy and histopathologic analysis.5 OSCC is generally treated with surgical, radiotherapy, chemotherapy, or combination. The treatment option depends on the site, size, and stage of the primary cancer. Besides, patient cooperativeness, nutritional intake, and ability to sustain the invasive treatment also influence the treatment success. Early-stage tumors can be treated by radiotherapy or surgery whereas in more severe stage, surgery is cooperated with adjuvant chemoradiotherapy.2 However the OSCC therapy causes subsequent cell death, ineffective long-term therapy, and infection risk on surgical site.6,7
One of the innovations as an OSCC therapy is the combination of curcumin-quercetin loaded nanostructured lipid carriers by downregulating AKT/PI3K signaling pathway. Curcumin has the most abundant polyphenol compound derived from Curcuma longa besides quercetin is a flavonoid derived from Allium cepa. The bioactive combination of curcumin-quercetin has low solubility hence encapsulated by nanoparticles is necessary.8,9
Nanostructured lipid carriers (NLCs) can enhance loading capacity and improve stability of curcumin-quercetin, biocompatible, and enhance the efficiency of site specific targeting.10 The anticancer role of curcumin-quercetin loaded NLCs by downregulating the pathway of protein kinase B (AKT)/phosphoinositide 3-kinase (PI3K) that manifests in cell cycle arrest at the G1/G2/M cell phase, regulates forkhead box protein 01 (FOXO-1) and p53 promoting cell apoptosis, and decrease expression of nuclear factor kappa beta (NF-κβ) expression can induce apoptosis and inhibit metastasis of OSCC.11,12 Administration of the combination of curcumin-quercetin loaded NLCs by injection targets the OSCC cell.
Oral Squamous Cell Carcinoma:
Pathogenesis of oral squamous cell carcinoma (OSCC) is arised from various mutations resulting in neoplastic transformation of the normal cell at a specific site. The predisposing factors of OSCC (tobacco smoking, alcohol consuming, betel chewing/areca nut, genetic susceptibility, and others) act as carcinogens initiate overexpression of TGF-α (transforming growth factor-alpha) following the progressive growth of epithelium cells.14 TGF-α induces the proliferation of cells by binding to EGFR (epidermal growth factor receptor) and stimulates angiogenesis that suggesting having rapid proliferation and instability of the epithelium dysplasia.13 EGFR promotes phosphorylation of some tyrosine residue. The phosphorylated tyrosine SERCA is the binding site for various signal transducers that are able to trigger the Ras. The binding of GTP thus leading to the activation of Ras. Ras-GTP binds to several effector to upregulate signaling pathways that controls proliferation, survival, and differentiation of cells.14 Ras-GTP has the potential to regulate the mitogen-activated protein kinase (MAPK) and AKT/PI3K pathways.15
AKT/PI3K Signaling Pathway:
AKT is a protein residue in the cytoplasm of the cells. The activation of AKT manifests in the decrease of pro-apoptotic proteins such as Bcl-2-associated death promoter (Bad) and Bcl-2-associated X protein (Bax). Downregulating of Bad stimulates the activation of anti-apoptotic B-cell lymphoma extra-large (Bcl-xL) thus inhibiting the apoptotic process. AKT also inhibits caspases that directly involved in apoptosis and FOXO-1 plays a role as a transcription factor and regulates pro-apoptotic protein expressions.16 PI3K is a heterodimer that controls activation of such proinflammatory pathway and activates NF-κβ that increase expression of cytokines and chemokines especially IL-6, a cytokine that stimulates a pro-tumor microenvironment and provides tumor progression.17 AKT/PI3K also disrupts the p53 signaling pathway then manifests in progression to the invasive carcinoma.13,16
Curcumin:
Curcumin is the main polyphenolic compound found in Curcuma longa L. or turmeric with the amount 75% that has anti-inflammatory, anti-oxidant, and anti-cancer pharmacological effects. Curcumin has low solubility and is unstable in alkaline conditions, so it requires a drug carrier to increase its bioavailability and stability.18 Preclinical and clinical studies have shown that curcumin can be used as a cancer therapy because it is a natural compound and acts as targets of multiple molecules to selectively destroy cancer cells with low toxicity.19 Curcumin induces cell apoptosis by inhibiting the regulation of signal transducer and activator of transcription 3 (STAT3), activator protein 1 (AP-1), cyclooxygenase II (COX-2), nitric oxide synthase, and matrix metalloproteinase-9 (MMP-9). Curcumin downregulates NF-kB and interleukin-6 (IL-6)-mediated STAT3 phosphorylation, thereby inhibiting cancer cell proliferation.20
Quercetin:
Quercetin is a bioflavonoid found in Allium cepa or onion. Quercetin has anti-inflammatory, antioxidant, anti-cancer, and anti-allergic activities. Quercetin has strong anticarcinogenic properties, namely as an inductor of apoptosis, antiproliferation and growth factor suppression of various cancer cells.21 Quercetin displays anti-cancer effects based on its binding to cellular receptors and proteins.22 In increasing the bioavailability of quercetin, it is enhanced with nanoparticles as a drug carrier.23 Quercetin induces a pro-apoptotic effect through its antioxidant effect and BCL-2 protein. In addition, quercetin inhibits metabolic process and induces cell death via apoptosis with increase of BAX expression followed by decrease of anti-apoptotic protein expression. Quercetin activates cell death domains leading to activation of FAS and FADD manifests in caspase-8 activation then inducts cell death in cancer cell lines.21
Nanostructured lipid carriers:
Nanostructured lipid carriers (NLCs) are the second generation of lipid-based nanoparticles. Manufacture of NLCs are formed by lipids (solid and liquid) and emulsifiers. NLCs are biodegradable, non-toxic and biocompatible. NLCs have high bioavailability, higher drug encapsulation, and structure that provides higher space for drug loading.25,26 NLCs have characteristics in terms of morphology, internal structure, dimensional distribution and encapsulation results.27
Curcumin-quercetin loaded Nanostructured lipid carriers:
Curcumin-quercetin loaded NLCs are injected into the body then reach the target cells. This combination then encapsulates releasing curcumin-quercetin. Curcumin decreases the expression of AKT, PI3K and its downstream proteins, mTOR, p70 S6K and p85 S6K in SCC-9 and FaDu cell line. On the other side, adding quercetin 50 mg/kg is able to decrease the expression of AKT and inhibits its phosphorylation process in MCF-7 cell culture.28,29
The AKT/PI3K signaling pathway is considered as a strong cell cycle inductor, inhibitor of pro-apoptotic protein expression, and plays an important role in OSCC metastasis. Inhibition of the pathway suppresses the activation of GSK-3β by disrupting the phosphorylation process at Ser 9 of GSK-3β. This condition manifests in inhibition of phosphorylation process at Thr 286 of cyclin D1 and prevents phosphorylation of cyclin E1 in Thr380 and manifests in the arrest of the G1/S phase.30-36 Lowering of p27 expression leads to a decrease of cyclin A.37,38 The decrease of cyclin A disrupts the formation of cyclin A-cyclin B leads to the G2/M phase arrest.39
Downregulating of AKT/PI3K signaling pathway is able to prevent the phosphorylation process of AKT in MDM2 leads to loss of MDM2 stability and manifests in an increase of p53.40,41 This condition is also followed by the increase of FOXO-1 leads to the increase of PUMA and Noxa expression and decrease of Mcl-1, Bcl-2, and Bcl-xL so that the expression of Bim and Bak increases.12,42-48 This condition is followed by the increase of Bid and activation of caspase-8 by activation of FAS and FADD then cleaves Bid into tBid thus leading to the tBid-Bak interaction. This condition induces Bak oligomerization then Bak induces Bax translocation from the cytoplasm into the outer mitochondrial membrane and forms heteromer formation leads to the decrease of mitochondrial membrane potential (∆Ψm) and formation of pores in mitochondria.21,49-59
The formation of mitochondrial pore induces cytochrome c release and SMAC/Diablo from the inner mitochondrial membrane to the cytoplasm. This condition is also supported by E2F expression, which leads to Apaf-1 synthesis. Apaf-1 then oligomerizes with cytochrome c to form an apoptosome. This protein then interacts with caspase-9 through the caspase recruitment domain and induces active site formation of caspase-3. In this process, caspase-3 activation is also maintained by the presence of SMAC/Diablo and Htr2/Omi to prevent the activity of XIAP that potentially disrupts the caspase-3 mediated apoptosis process.54,60-65 Activation of caspase-3 increases the hydrostatic pressure of the cell followed by repetitive cell contraction by actomyosin manifests in membrane blebbing. This continuous process leads to cell retraction then performs an apoptotic body covered with organelles and cellular materials. The apoptotic body would be phagocytized by the dendritic cell.66
Downregulating of this pathway decreases STAT3 expression then NF-kB expression is lowered. This manifests in the decrease of MMP-2/9 causing cell-membrane adhesion and inhibition of extracellular matrix degradation, preventing the cancer cell to migrate out of the basal membrane so that the metastatic process is suppressed.20,67-70
CONCLUSION:
According to the literature review, combination of curcumin-quercetin loaded NLCs is potential as a biomaterial candidate for OSCC therapy by downregulating AKT/PI3K signaling pathway. Future research about the natural biomaterial role in OSCC therapy especially curcumin-quercetin loaded NLCs should be conducted to discover a new way to treat OSCC with low side effects. The importance of using a specific signaling pathway of OSCC in targeted drug therapy should be conducted to reveal the most significant way to cure OSCC is still needed.
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Received on 24.11.2021 Modified on 11.02.2022
Accepted on 30.03.2022 © RJPT All right reserved
Research J. Pharm. and Tech 2022; 15(11):5353-5358.
DOI: 10.52711/0974-360X.2022.00902