臺灣博碩士論文加值系統

Zerumbone (Zer) is a sesquiterpene phytochemical substance extracted from the subtropical plant Zingiber zerumbet's rhizomes. It has been scientifically investigated to have anti-oxidant, anti-inflammatory, and anti-cancer characteristics in addition to other biological actions. This work reviewed the molecular basis behind Zer's in vivo and in vitro anti-cancer potency at different doses of Zer (15–45 μM) on A375 and A2058 (15–60 μM) melanoma cells. Zer substantially reduced the viability of the cells. The triggering of ROS activation, Caspase-3 activation, PARP cleavage, and Bax/Bcl-2 dysregulation, LC3-II accumulation, AVOs appearance, and Beclin-1/Bcl-2 dysregulation and signaling by caspase-3 and LC3-II accumulation was correlated, highlighting the mechanism of apoptotic and autophagic activation. Elevated LC3-II appearance and AVO synthesis were evidence of Zer-induced autophagy. Paradoxically, 3-MA and CQ potentiated Zer-mediated cell death, referring to the potential significance of autophagy as a cell death approach. Additionally, A2058 and A375 cells treated with Zer generated more intracellular ROS, while antioxidant NAC controlled apoptosis and autophagy and immediately turned back autophagic channels. Intriguingly, the PARP cleavage and Beclin-1/Bcl-2 upregulating were activated to promote Zer-controlled apoptotic signaling and autophagic responses. Based on in-vivo investigations, Zer dramatically reduced tumor progression in nude mice with A2058-xenografts; in mice with A2058 xenografts treated with Zer, a Western blot revealed activation of apoptosis (PARP cleavage and Bcl-2 inhibition), and autophagy (LC3-II and Beclin-1) overexpression). The present findings revealed that the anticancer drug Zerumbone stimulates ROS-mediated apoptosis and autophagy in both melanoma cell lines.

ACKNOWLEDGEMENT 5
ABSTRACT 6
I. GRAPHICAL MECHANISM/ABSTRACT 7
7
ABBREVIATIONS: 11
1. INTRODUCTION 12
1.1 . THE CONVERSION OF TYPICAL MELANOCYTES INTO MELANOMA CELLS 16
1.2 . SYNTHESIS OF MELANIN 19
1.3 . THE SYNTHESIS OF ROS IN THE SKIN. 20
1.4 . THE COMPARATIVE DIFFERENCE AND SIGNIFICANCE OF A375 AND A2058 MELANOMA CELL LINES: 23
2. MATERIALS AND METHODS 25
2.1 REAGENTS 25
2.2. CELL CULTURE 26
2.3. MTT ASSAY 26
2.4. CELL LYSATE PREPARATION 26
2.5. WESTERN BLOTTING 27
2.6. ACRIDINE ORANGE STAINING 27
2.7. SIRNA TRANSFECTION 28
2.9. MEASUREMENT OF INTRACELLULAR ROS 28
2.10. IN VIVO EXPERIMENTS 29
2.11. XENOGRAFTING OF A375 OR A2058 CELLS 29
2.12 STUDY OF XENOGRAFT TUMORS EMPLOYING THE WESTERN BLOTTING APPROACH 29
2.13. STATISTICAL DATA ANALYSIS 30
3. RESULTS 31
3.1 ZER REDUCED CELL PROLIFERATION AND CELLULAR APPEARANCE IN BOTH CELLS 31
3.2 ZER IMPEDED COLONY FORMATION IN A375 AND A2058 CELLS. 31
AS THE CONCENTRATION OF ZER IMPROVED FROM 0–45 OR 0–60 µM, THE CAPACITY FOR A375 AND A2058 CELLS TO FORM COLONIES WERE REDUCED (FIG 2 A-B). IN BOTH CELL LINES, COLONY NUMBER WAS DRASTICALLY DECREASED WITH ZER (FIG 2 C-D). 31
3.3 IN BOTH MELANOMA CELLS, ZER PROMPTED APOPTOSIS. 31
3.4. IN A2058 AND A375 CELLS, ZER FAVORS THE FORMATION OF AUTOPHAGY AND APOPTOSIS. 32
3.5. ZER ENABLES MELANOMA CELLS TO DEVELOP AVOS ACCUMULATION 34
3.7 ZER ACTIVATED AUTOPHAGIC SIGNALING IN BOTH MELANOMA CELLS AS A MARKER OF CELL DEATH STRATEGY 35
3.8 IN A2058 AND A375 CELLS, ZER ACCELERATES DNA DISINTEGRATION AND TRIGGERS LATE APOPTOSIS. 35
3.9. RELATIONSHIPS INVOLVING THE EVENTS OF APOPTOSIS AND AUTOPHAGY 36
3.10 ZER-INDUCED APOPTOSIS IN BOTH MELANOMA CELLS WAS DIMINISHED BY AUTOPHAGIC DEGRADATION. 37
3.11. ZER ACCUMULATED ROS STIMULATION IN MELANOMA CELLS. 38
3.12. ROS DOWN-REGULATION BY NAC DETERMINED ZER-REGULATED APOPTOSIS AND AUTOPHAGY IN A375 OR A2058 38
3.13 ZER AND ZZ EXTRACTS REDUCED THE TUMOR WEIGHT AND VOLUME IN NAKED MICE. 39
3.13 AUTOPHAGY AND APOPTOTIC RESPONSES WERE LINKED TO ZER-MEDIATED AND ZZ EXTRACTS DECLINE IN TUMOR APPEARANCE AND TUMOR WEIGHT IN NAKED MICE. 40
3. DISCUSSION 41
4. SUMMARY 47
5. CONCLUDING REMARK 50
6. FUTURE STUDIES 51
1. EXPLORING THE DIVERSE BIO-CHEMICAL SIGNALING CHANNELS: 51
2. ASSESSING THE IMPACT OF THE SPECIFIC MICROENVIRONMENT ON THE EVOLUTION OF THE TUMOR: 51
3. OPTIMIZING THE PROCEDURE FOR DELIVERY OF THE ZERUMBONE: 52
4. THERAPIES THAT COMBINE SEVERAL DIFFERENT COMPONENTS: 52
5. PRECLINICAL/CLINICAL TRIALS: 53
7. GENERAL MECHANISTIC OVER-VIEW OF THIS STUDY 55
1. STRUCTURE OF ZER AND ITS DIFFERENT MOLECULAR/SIGNALING TARGETS TO TREAT SEVERAL DISEASES. 55
56
2. MECHANISM OF MELANIN GENERATION AND ITS MOLECULAR STRUCTURE 56
3. DESCRIPTION OF A COLLECTION OF METABOLIC PROCESSES THAT RESULT IN THE PRODUCTION OF HUMAN MELANIN, (A) PHEOMELANIN, (B) EUMELANIN AND (C) BASIC MECHANISM OF MELANIN SYNTHESIS. 57
4. STEPS AND MECHANISM OF AUTOPHAGIC EVENTS 58
5. ZERUMBONE ACTIVATED APOPTOTIC SIGNALING MECHANISM. 59
7. MECHANISM OF ROS PRODUCTION AND ZER RESULT IN CELLULAR DAMAGE AND APOPTOTIC SIGNALING CELL DEATH. 61
8. MECHANISM OF ZER TRIGGERED AN AUTOPHAGIC AND APOPTOTIC RESPONSE MEANWHILE APOPTOSIS INHIBITS AUTOPHAGY LEADING TO ZER STIMULATED CELL DEATH. 62
8. FIGURE AND LEGENDS 63
FIG. 1. ZERUMBONE (ZER) INHIBITS CELL PROLIFERATION MELANOMA CELLS. 63
FIG. 2. ZER LIMITED COLONY APPEARANCE IN A375 AND A2058 CELLS. 64
FIG. 3. IN A375 AND A2058, ZER INITIATED THE APOPTOTIC MECHANISM. 65
FIG. 4. ZER INDUCED LC3-II STIMULATION LEADING TO EXHIBIT AUTOPHAGY IN A375 AND A2058 CELLS. 66
FIG. 5. ZER TRIGGERS AVO ACCUMULATION IN MELANOMA CELLS. 67
FIG. 6. IN A375 AND A2058 CELLS, ZER DOSE-DEPENDENTLY UPREGULATED BAX/BCL-2 LEVELS. 68
FIG. 7. ZER FAVORS AUTOPHAGY, WHICH PRIMARILY SERVES AS A MODE OF CELL DEATH, IN A375 AND A2058 CELLS. 69
FIG. 8. IN A375 OR A2058 CELLS, ZER PROMOTED LATE APOPTOTIC CONTROLLED/PROGRAMMED CELL DEATH. 70
FIG. 9. THE ASSOCIATION INVOLVING BOTH AUTOPHAGIC AND APOPTOTIC CELL DEATH RESULTED FROM ZER IN A375 CELLS. 71
FIG. 10. ZER IN A375 CELLS DEVELOPED THE AUTOPHAGIC AND APOPTOTIC CROSS-LINK AS A CELL DEATH PROCESS IN A2058. 72
FIG. 11. ZER TRIGGERS ROS APPEARANCE IN A375 AND A2058 CELLS. 73
FIG. 12. ZER TRIGGERS ROS REGULATED AUTOPHAGIC AND APOPTOTIC CHANNELS IN A375 OR A2058 CELLS. 74
FIG. 13. ZER AND ZZ DISPLAYED A TUMOR-SUPPRESSIVE EFFECT IN XENOGRAFTED NAKED MICE. 75
FIG. 14. ZER AND ZZ INHIBITED A375 AND A2058 XENOGRAFTED TUMORS IN MICE. 76
9. REFERENCE: 78

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