{"id":58396,"date":"2024-06-25T11:58:23","date_gmt":"2024-06-25T11:58:23","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=58396"},"modified":"2024-07-03T16:40:40","modified_gmt":"2024-07-03T16:40:40","slug":"targeting-autophagic-pathway-in-oral-cancer-therapy-through-phytoconstituents-a-short-review","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no2\/targeting-autophagic-pathway-in-oral-cancer-therapy-through-phytoconstituents-a-short-review\/","title":{"rendered":"Targeting Autophagic Pathway in Oral Cancer Therapy Through Phytoconstituents: A Short Review"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

The mechanism of autophagy is a\ncellular recycling process that attempts to maintain the removal of unwanted\nproteins as well as unhealthy or old organelles1<\/sup>. The molecular\nmechanics of the process of autophagy through various types of actions are\nleast specified2.<\/sup> There are several chemotherapy-resistant\nmechanisms available which include cell death processes like autophagy and\napoptosis, multi-drug resistance, cancer cell heterogeneity, and cancer\nmicro-environment pressure-induced genetic or epigenetic modifications. Along\nwith the above factors, alterations in two self-disparaging procedures(apoptosis\nand autophagy) might initiate better therapies3,4 <\/sup>for cancer\ntreatment. Phytochemicals\ntrigger different cell death pathways, such as apoptosis, autophagy, or pyroptosis.<\/p>\n\n\n\n

Numerous studies have already been performed to date to explain the detailed mechanism of the use of phytochemicals in these cell-signaling pathways. The potential purpose of phytochemicals during the process of apoptosis, as well as autophagy, was analyzed elaborately by Deng5<\/sup> and his co-workers, in 2019. As most studies emphasized the apoptotic pathway, the least reports are found on autophagy. So, this study attempts to summarize the use of phytochemicals in various autophagy pathways treating oral cancer.<\/p>\n\n\n\n

Autophagy in carcinoma pathway<\/strong><\/strong><\/p>\n\n\n\n

Autophagy conserves as a lively interconnection in\ncell protection and a cytostatic association in carcinoma cell development6<\/sup>.\nThe procedure introduced by the production of phagophore assemblage sites(PAS)6<\/sup>,\nPhosphatidylinositol 3-phosphate(PI3K) along with the endoplasmic reticulum\/ER,\nwas found to have a crucial function in the configuration of  PAS7.<\/sup> Adenosine Monophosphate activated\nprotein kinase(AMPK), mammalian target of rapamycin shortly termed \u2018mTOR\u2019 and\nunc-51  autophagy activating kinase-1(ULK1)\nfound making easy phagophore development through autophagy initiation8<\/sup>,\nby the help of  Vps15\/p150, Vps34 and\nBeclin-1 in phagophore configuration9<\/sup>. The formation of phagophores,\nresults in phagocytosis, consequently ending in elongation and sealing the\nmembrane meant for the formation of autophagosome10<\/sup>. Adult\nautophagosomes attach with lysosomes, resulting in the\ndevelopment of autolysosomes2<\/sup>. Thus autolysosomes can be demolished\nby acidic hydrolases, help in additional recycling metabolism and consequently\nconserve cellular equilibrium.        <\/p>\n\n\n\n

However, mTOR is very significant in autophagy by defending or\nactivating oncogenic cells. Chemotherapy drugs hold back cancer cells by\naltering the pathway of autophagy. So autophagy can be termed either a cellular\nexistence or demise system11 <\/sup>and displays a vital position in\nmaintaining metabolic adjustment in cancerous cells12<\/sup>. AMPK and mTOR\nhave been recognized to be the most important signaling molecules that enhance\nautophagy through amino acids and the level of glucose8<\/sup>. Anyways,\nspecified metabolites like palmitate, oxygen concentration, ATP to ADP ratio,\nparticular levels of certain amino acids, ROS, growth factors as well as\noncogenes control autophagy instigation and autophagosome construction. It has\nbeen confirmed by Youn13<\/sup>, that genes like Phosphatase and Tensin\nhomolog deleted on chromosome 10(PTEN), Beclin-1, and Death associated protein\nkinase 1(DAPK 1) are cancer-suppressing and regulate the autophagy pathway. The\nexpressed PTEN may endorse downregulation of the PI3K\/AKT pathway, disturbing\ncancer augmentation by invigorating autophagy.<\/p>\n\n\n\n

Development of autophagy in oral carcinoma<\/strong><\/p>\n\n\n\n

Autophagy is an actively impartial cellular process where unwanted\nnonfunctional cellular molecules break down or disintegrate by synthesis with\nlysosomes6<\/sup>; This cellular procedure plays a key role in regulating\ncell function and homeostasis. So autophagy conserves a dynamic relation in\ncell protection mechanism and a cytostatic linkage in tumor cell development6<\/sup>.<\/p>\n\n\n\n

Autophagy-related genes like ATG7 take part in the covalent bonding between ATG5 – ATG12 in the membrane of autophagosome as an E1-like ubiquitination activase. Except, ATG8, recognized as microtubule-associated protein 1 light chain 3 (MAP1LC3 or LC3), is decisive for autophagy. Autophagy having dual activity can either enhance or restrict the onset of tumorigenesis. According to Saha14<\/sup>, autophagy may enhance the growth of tumor cells supplying nutrients in the later stage, still in the early stage, a long non-coding RNA FLJ22447 restricts autophagy of the cancer-associated fibroblasts (CAFs) and regulates the autophagic filth of IL33, where CAFs produce sufficient IL33 for the propagation of OSCC cells.  Researchers like Zhang15<\/sup> established that the neutrophil gelatinase-associated calcitonin (NGAL) gene activates mTOR, by blocking autophagy and enhancing OSCC. The mTOR protein kinase is a key downbeat controller of autophagy16<\/sup> and controls numerous cell signaling pathways affecting cell growth, most of which with tyrosine kinase activity exhibit downstream growth factors. Structural activation of RAS, PI3K, AKT(activation mutation) and PTEN(inactivation mutations) are regularly found in cancer development. So Poillet-Perez and White17<\/sup> suggested autophagy inhibition may endorse tumor intensification.  <\/p>\n\n\n\n

 Then autophagy-mediated Oral\ncarcinoma can be distinguished as ROS-dependent NUPR1-mediated autophagy,\nmicroRNA-mediated autophagy, or long Non-coding RNA-mediated autophagy.\nAutophagy in oral carcinoma treatment was established by various researchers in\ndifferent ways. Some established CerS6 to enhance cisplatin-associated\nchemotherapy18<\/sup>, some regulated the ATG gene to block the oral\ncarcinoma development and some tried to modify autophagy-related noncoding RNA\nto prevent oral carcinoma19<\/sup>.  <\/p>\n\n\n\n

Phytochemicals involved in cancer through\nautophagy<\/strong><\/p>\n\n\n\n

The Table. 1 gives a brief idea about some popular plant derivatives\nused in cancer therapy through autophagy.<\/p>\n\n\n\n

Table 1: Some popular plant derivatives used in cancer therapy through autophagy<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Sl. No.<\/strong><\/p>\n<\/td>\n

\n

Name of the phyto chemicals<\/strong><\/p>\n<\/td>\n

\n

Plant source<\/strong><\/p>\n<\/td>\n

\n

Cancer type<\/strong><\/p>\n<\/td>\n

\n

Signaling pathway<\/strong><\/p>\n<\/td>\n

\n

References<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

1<\/p>\n<\/td>\n

\n

Gintonin (Glycoprotein)<\/p>\n<\/td>\n

\n

Panax ginseng<\/em><\/p>\n<\/td>\n

\n

Central Nervous System<\/p>\n<\/td>\n

\n

Akt\/mTOR\/p70S6K-mediated pathway<\/p>\n<\/td>\n

\n

20<\/p>\n<\/td>\n<\/tr>\n

\n

2<\/p>\n<\/td>\n

\n

Allicin( sulphur compound)<\/p>\n<\/td>\n

\n

Allium sativum<\/em><\/p>\n<\/td>\n

\n

Lung cancer<\/p>\n<\/td>\n

\n

A549 cells by ROS accumulation and facilitating S\/G2-M phase arrest<\/p>\n

<\/p>\n

PI3K\/mTOR signaling pathway<\/p>\n<\/td>\n

\n

\n<\/p>

21<\/p>\n

\n<\/p>

\n<\/p>

22<\/p>\n

\n<\/p><\/td>\n<\/tr>\n

\n

3<\/p>\n<\/td>\n

\n

Curcumin(polyphenolic compound)<\/p>\n<\/td>\n

\n

Curcuma longa L.<\/em><\/p>\n<\/td>\n

\n

Multiple cancers<\/p>\n<\/td>\n

\n

Autophagy in NSLCA549 cells<\/p>\n

<\/p>\n

Increased ROS and DNA damage, phosphorylation of ERK1\/2 and p38 AMPK, inhibited Akt and P54 JNK<\/p>\n<\/td>\n

\n

23<\/p>\n

\n<\/p>

\n<\/p>

24<\/p>\n<\/td>\n<\/tr>\n

\n

4<\/p>\n<\/td>\n

\n

Apigenin(Flavonoid)<\/p>\n<\/td>\n

\n

Justicia gendarussa<\/em><\/p>\n<\/td>\n

\n

Hepatocellular carcinoma<\/p>\n<\/td>\n

\n

PI3K\/Akt\/mTOR pathway<\/u><\/p>\n

 <\/u><\/p>\n

 <\/u><\/p>\n

Kinase pathway\/cell cycle at G2\/M phase<\/p>\n<\/td>\n

\n

25<\/p>\n

\n<\/p>

\n<\/p>

\n<\/p>

26<\/p>\n<\/td>\n<\/tr>\n

\n

5<\/p>\n<\/td>\n

\n

Aspalathin(polyphenolic compound<\/p>\n<\/td>\n

\n

Aspalathus linearis<\/em><\/p>\n<\/td>\n

\n

Prostate cancer<\/p>\n<\/td>\n

\n

AMPK and Fox pathways<\/p>\n<\/td>\n

\n

27<\/p>\n<\/td>\n<\/tr>\n

\n

6<\/p>\n<\/td>\n

\n

Hispolon (Polyphenol)<\/p>\n<\/td>\n

\n

Phellinus igniarius <\/em>(L.)<\/p>\n<\/td>\n

\n

Naso-pharyngeal cancer<\/p>\n<\/td>\n

\n

ERK pathway<\/p>\n<\/td>\n

\n

28<\/p>\n<\/td>\n<\/tr>\n

\n

7<\/p>\n<\/td>\n

\n

Toxicarioside O<\/p>\n<\/td>\n

\n

Antiratoxicaria<\/em><\/p>\n<\/td>\n

\n

Colorectal cancer<\/p>\n<\/td>\n

\n

Akt\/
mTOR pathway<\/p>\n<\/td>\n

\n

29<\/p>\n<\/td>\n<\/tr>\n

\n

8<\/p>\n<\/td>\n

\n

Berberine(Alkaloid)<\/p>\n<\/td>\n

\n

turmeric, Oregon grape, goldenseal, and European barberry.<\/p>\n<\/td>\n

\n

Colon,Pancreas, Ovarian<\/p>\n

And breast cancer<\/p>\n<\/td>\n

\n

AMPK\/mTOR\/ULK1 pathway<\/p>\n<\/td>\n

\n

30<\/p>\n<\/td>\n<\/tr>\n

\n

9<\/p>\n<\/td>\n

\n

Celastrol(tri terpenoid)<\/p>\n<\/td>\n

\n

Tripterygium wilfordii<\/em><\/p>\n<\/td>\n

\n

Prostate cancer<\/p>\n<\/td>\n

\n

AR signaling pathway<\/p>\n<\/td>\n

\n

31<\/p>\n<\/td>\n<\/tr>\n

\n

10<\/p>\n<\/td>\n

\n

Evodiamine(quinolone alkaloid )<\/p>\n<\/td>\n

\n

Evodia rutaecarpa<\/em><\/p>\n<\/td>\n

\n

Multiple cancer<\/p>\n<\/td>\n

\n

 Beclin-1 and Bax expression  for upregulation and<\/p>\n

Bcl-2 downregulation<\/p>\n<\/td>\n

\n

32<\/p>\n<\/td>\n<\/tr>\n

\n

11<\/p>\n<\/td>\n

\n

Fisetin(flavonoid)<\/p>\n<\/td>\n

\n

Strawberries, apples, persimmons, onions and cucumber<\/p>\n<\/td>\n

\n

Prostate cancer<\/p>\n<\/td>\n

\n

TOR signaling pathway<\/p>\n<\/td>\n

\n

33<\/p>\n<\/td>\n<\/tr>\n

\n

12<\/p>\n<\/td>\n

\n

Genistein<\/p>\n

(Isoflavon)<\/p>\n<\/td>\n

\n

legumes,<\/p>\n<\/td>\n

\n

Ovarian cancer<\/p>\n<\/td>\n

\n

Akt
phosphorylation<\/p>\n<\/td>\n

\n

34<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Phytochemicals affecting <\/strong>oral cancer therapy through autophagy<\/strong><\/p>\n\n\n\n

F.S. Yu35<\/sup> reported on the cytotoxicity of tetrandrine over HSC-3 human oral cancer cells through autophagy and apoptosis. Tetrandrine improved LC3-I and -II expression initiating autophagy in HSC-3 cell lines. So tetrandrine-mediated autophagy in HSC-3 cells leads to cell fatality through PARP, caspases(3,8,9)\/Becline I\/LC3-I\/II signaling pathways. The autophagy induced by tetrandrine through the Wnt\/\u03b2-catenin pathway was also established by Zhang36<\/sup>. Chang37<\/sup> for the first time revealed the resveratrol-mediated cell autophagy as well as apoptosis in cisplatin-resistant human oral tumor cells. They suggested resveratrol initiated autophagy vesicle formation, AVOs, and LC3B(Auto phagosome formation) in CAR cells. This also affects mRNA expression of genes like Beclin-1, LC3-II, Atg5, and Atg12, <\/em>and is responsible for autophagy in CAR cells. This improves autophagy-involved proteins like Beclin-1, LC3-II, PI3K class III, 3-MA (an inhibitor of PI3K class III), and Atg complexes repressed the autophagic vesicle configuration by resveratrol. Chu38<\/sup> demonstrated the action of thymoquinone(TQ) against 4 types of oral carcinoma cell lines (SAS, SCC-4, OC2, and SASVO3) of which SASVO3 cells were found to be mostly affected. Expression of autophagy-related proteins like Beclin-1, Rubicon, Class III, PI3K family, and Atg complex proteins, initiated autophagy by the formation of the autophagosome. Then LC3-I is attached to the lipid phosphatidyl ethanolamine and LC3-II is produced which is, an indicator of autophagy.  mTOR is concerned with TQ-induced autophagy. Galangin stimulated autophagy by overexpressed genes like LC3I, LC3II, and Beclin 1 was demonstrated by Wang39<\/sup> , which ended that galangin may cause human laryngeal carcinoma cell death, contributing to tumor suppression. Autophagy initiation was identified by Beclin-1 enhancement and p62 degradation which concluded that baicalein treatment induced autophagy in the OSCC cells. According to Li40<\/sup>, baicalein outstandingly amplified caspase-3 activity after repressing autophagic flux. This disclosed that baicalein-initiated autophagy reticence enhanced Cal27 cells to baicalein-initiated cell fatality by apoptosis. The autophagic pathways of the above-mentioned phytoconstituents are represented in Figure 1. <\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 1: Depicts the different phytochemicals involved in autophagy through different pathways in oral cancer.<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Conclusions and Future Perspectives<\/strong><\/p>\n\n\n\n

Autophagy is an extremely multifaceted metabolic procedure that performs a decisive position in the body’s resistance to diseases. It shows a bifurcated effect over oral cancer. The outcome of autophagy on the incidence and expansion of oral cancer is mostly by the expression of autophagy-related genes. Plants and their bioactive products, which are rewards from mother nature to the human race, showed considerable anticancer activity and possess the capability to hold back the initiation and expansion of oral cancer, adopting mostly the apoptotic pathway. Phytochemicals in the pathway of apoptosis are widely studied in cancer therapeutics especially oral carcinoma, whereas the study of autophagy is almost neglected. That\u2019s why there is a need for exploration of autophagic mechanisms and an explanation of the connection between the signaling pathway of autophagy and oral cancer. So we tried to put an insight into the process of autophagy in OSCC by the phytoconstituents which may help the researchers in the development of novel drugs. <\/p>\n\n\n\n

Acknowledgment<\/strong><\/p>\n\n\n\n

We would like to thank IMS and SUM Hospital of SOA Deemed to be University for the use of their facilities. The authors are grateful to Professor Manojranjan Nayak, the president of SOA Deemed to be University, for supporting the study.<\/p>\n\n\n\n

Conflict of Interests<\/strong><\/p>\n\n\n\n

The authors declare no conflict of interest. <\/p>\n\n\n\n

Funding Sources<\/strong><\/p>\n\n\n\n

There is no funding Sources<\/p>\n\n\n\n

Data availability<\/strong><\/p>\n\n\n\n

Data was collected from Scopus, Science direct, Elsevier, PubMed and Google Scholar.<\/p>\n\n\n\n

Author contributions<\/strong><\/p>\n\n\n\n

SS performed literature searches and wrote the manuscript. SKB reviewed the manuscript. RB edited and designed the manuscript. All authors contributed to manuscript revision, and approved the submitted version.<\/p>\n\n\n\n

Ethical approval<\/strong><\/p>\n\n\n\n

Not applicable.<\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

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