Curcumin and metformin‐mediated chemoprevention of oral cancer is associated with inhibition of cancer stem cells

Siddappa, Gangotri; Kulsum, Safeena; Ravindra, Doddathimmasandra Ramanjanappa; Kumar, Vijaya; Raju, Nalini; Raghavan, Nisheena; Sudheendra, Holalugunda Vittalamurthy; Sharma, Anupam; Sunny, Sumsum; Jacob, T. R.; Kuruvilla, Binu T.; Benny, Merina; Antony, Benny; Seshadri, Mukund; Lakshminarayan, Padma; Hicks, Wesley L.; Suresh, Amritha; Kuriakose, Moni Abraham

doi:10.1002/mc.22692

Cited by 57 publications

(45 citation statements)

References 51 publications

(59 reference statements)

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“…The 4NQO model was established and the mice were evaluated at different stages for clinical and histological progression of disease as described previously . Explants from 6th, 14th, and 16th week were successfully propagated in vitro and primary cell lines were developed (Figure A).…”

Section: Resultsmentioning

confidence: 99%

“…In our study, Notch1 was deregulated in the epithelial cell lines and an inhibition of its activity using GSI led to a significant decrease in CSC and dysplastic profile, indicating its significance in dysplastic progression of oral cancer. Our previous study had demonstrated the anti‐dysplastic, anti‐CSC effect of Curcumin and Metformin in the dysplastic cells, Notch1 downregulation is one of the downstream effects of this treatment, in addition to the inhibition of multiple other pathways. Whether addition of PZ0187 to either of these drugs/combination will increase the effect remains to be explored.…”

Section: Discussionmentioning

confidence: 98%

“…The role of CSCs in oral carcinogenesis has been investigated with multiple concepts proposed to explain their role in tumor initiation, subsequent field cancerization, and recurrence . Our recent study reported an association between oral cancer development and CSC behavior in a 4NQO mice model . In this study, we described development of in‐vitro cell line models from the 4NQO induced mice as a surrogate model for dysplastic progression of oral cancer and investigated the role of CSCs and niche in oral carcinogenesis using this model.…”

Section: Discussionmentioning

confidence: 99%

“…The mice model was generated using the 4‐Nitroquinoline‐1‐oxide (4NQO) (Figure A); C57Bl/6 (30 g; 4‐6 weeks old) female mice were fed orally with 4NQO (50 μg/mL, Sigma Aldrich, St. Louis, MO) and a subset of animals ( n = 5) were sacrificed at every 2 weeks. Tongue samples were collected [DMEM‐F12, 10% fetal bovine serum, (Gibco, Waltham, MA)], decontaminated (betadine), and processed further in culture media (20% FBS, 2× Penicillin‐Streptomycin (Himedia, Bengaluru, Karnataka)).…”

Section: Methodsmentioning

confidence: 99%

“…The specificity of the product was ascertained by the melting curve analysis. Primer efficiency was assessed using the slope of the linear regression model as previously described . 18s Ribosomal RNA ( Rn18s ), β2‐Microglobulin ( β2m ), and Hypoxanthine‐guanine phosphoribosyltransferase 1 ( Hprt1 ) were assessed using RefFinder and the best Reference Genes (RGs) ( n = 2) were selected for expression profiling, the relative change in expression was evaluated using their geometric mean.…”

Section: Methodsmentioning

confidence: 99%

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Cancer stem cells and fibroblast niche cross talk in an in‐vitro oral dysplasia model

Kulsum

Raju²,

Raghavan³

et al. 2019

Molecular Carcinogenesis

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Understanding the cellular interactions during oral carcinogenesis has the potential to identify novel prognostic and therapeutic targets. This study aimed at investigating the cancer stem cell (CSC)‐fibroblast niche interactions using in‐vitro dysplastic cell line models developed from different stages of 4NQO‐induced oral carcinogenic mice model. The spontaneously transformed epithelial cells (DysMSCTR6, 14 and 16) were developed from three time points (mild/moderate/severe), while two fibroblast cell lines (FibroMSCTR12, 16) were developed from moderate and severe dysplastic tissue. The epithelial (Epcam+/Ck+) and the fibroblast cell lines (Vimentin+/α‐SMA+/Ck‐) were authenticated and assessment of cells representing progressive grades of dysplastic severity indicated a significant increase in dysplastic marker profile (P < 0.05). Evaluation of the CSC characteristics showed that an increase in expression of Cd133, Cd44, Aldh1a1, Notch1, and Sox2 was accompanied by an increase in migratory (P > 0.05) and colony formation capacity (P > 0.005). Targeting Notch1 (GSI inhibitor PZ0187; 30 μM), showed a significant reduction in cell proliferation capacity (P < 0.05) and in the dysplastic marker profile. Further, Notch1 inhibition resulted in down regulation of Cd133 and Aldh1a 1 (P < 0.05) and a complete abrogation of colony formation ability (P < 0.0001). The effect of niche interactions evaluated using FibroMSCTR12‐conditioned media studies, revealed an enrichment of ALDH1A1+ cells (P < 0.05), induction of spheroid formation ability (P < 0.0001) and increased proliferation capacity (3.7 fold; P < 0.005). Although PZ0187 reduced cell viability by ∼40%, was unable to abrogate the conditioned‐media induced increase in proliferation capacity completely. This study reports a Notch‐1 dependent enrichment of CSC properties during dysplastic progression and a Notch‐1 independent dysplastic cell‐fibroblast interaction during oral carcinogenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Cancer stem cells and fibroblast niche cross talk in an in‐vitro oral dysplasia model

Kulsum

Raju²,

Raghavan³

et al. 2019

Molecular Carcinogenesis

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Chemoprevention of oral cancer: A review and future perspectives

et al. 2023

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Background: Oral cancer causes significant morbidity and mortality. Chemoprevention utilizes medication or natural compounds to reverse oral premalignant lesions and to prevent second primary tumors. Methods: A comprehensive PubMed database and Cochrane Library search from 1980 to 2021 was performed using the keywords "leukoplakia," "oral premalignant lesion," and "chemoprevention."Results: Chemopreventive agents included retinoids, carotenoids, cyclooxygenase inhibitor, herbal extracts, bleomycin, tyrosine kinase inhibitors, metformin, and immune checkpoint inhibitors. Although some agents demonstrated effect in reducing premalignant lesions and preventing second primary tumors, the results among different studies were highly variable. Conclusions:The results of different trials, albeit inconsistent, provided substantial information for future studies. In the era of personalized medicine, future studies will focus on identifying specific biomarkers and molecular profile to monitor and to prevent malignant transformation. Larger trials are warranted to validate the effect of chemopreventive agents.

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Anticancer properties of tocotrienols: A review of cellular mechanisms and molecular targets

Marelli

Marzagalli

Fontana

et al. 2018

Journal Cellular Physiology

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Vitamin E is composed of two groups of compounds: α-, β-, γ-, and δ-tocopherols (TPs), and the corresponding unsaturated tocotrienols (TTs). TTs are found in natural sources such as red palm oil, annatto seeds, and rice bran. In the last decades, TTs (specifically, γ-TT and δ-TT) have gained interest due to their health benefits in chronic diseases, based on their antioxidant, neuroprotective, cholesterol-lowering, anti-inflammatory activities. Several in vitro and in vivo studies pointed out that TTs also exert a significant antitumor activity in a wide range of cancer cells. Specifically, TTs were shown to exert antiproliferative/proapoptotic effects and to reduce the metastatic or angiogenic properties of different cancer cells; moreover, these compounds were reported to specifically target the subpopulation of cancer stem cells, known to be deeply involved in the development of resistance to standard therapies. Interestingly, recent studies pointed out that TTs exert a synergistic antitumor effect on cancer cells when given in combination with either standard antitumor agents (i.e., chemotherapeutics, statins, "targeted" therapies) or natural compounds with anticancer activity (i.e., sesamin, epigallocatechin gallate (EGCG), resveratrol, ferulic acid). Based on these observations, different TT synthetic derivatives and formulations were recently developed and demonstrated to improve TT water solubility and to reduce TT metabolism in cancer cells, thus increasing their biological activity. These promising results, together with the safety of TT administration in healthy subjects, suggest that these compounds might represent a new chemopreventive or anticancer treatment (i.e., in combination with standard therapies) strategy. Clinical trials aimed at confirming this antitumor activity of TTs are needed.

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Curcumin and metformin‐mediated chemoprevention of oral cancer is associated with inhibition of cancer stem cells

Cited by 57 publications

References 51 publications

Cancer stem cells and fibroblast niche cross talk in an in‐vitro oral dysplasia model

Cancer stem cells and fibroblast niche cross talk in an in‐vitro oral dysplasia model

Chemoprevention of oral cancer: A review and future perspectives

Anticancer properties of tocotrienols: A review of cellular mechanisms and molecular targets

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