Synergistic Interactions of Atractylodes lancea Rhizome Compounds in the Treatment of Cholangiocarcinoma | Chapter 7 | Contemporary Research and Perspectives in Biological Science Vol. 3

 

Background: Cholangiocarcinoma (CCA)is the primary type of bile duct cancer with high morbidity and mortality, particularly in patients with advanced stages. Numerous studies have been carried out in efforts to discover effective cancer chemotherapeutic agents from plant sources with low toxicity. Treatment of CCA remains unsatisfactory due to the lack of sensitive and specific diagnostic tools for early detection and effective chemotherapeutics.

Purpose: The primary purpose of this study is to investigate cytotoxic interactions between the three major constituents of the rhizomes of Atractylodeslancea (Thunb)DC., i.e., β-eudesmol (BE), atractylodin (AT), and hinesol (HS) against CCA cell line. 

Methods: The bioactive constituents of AL rhizome under investigation, ie, BE, AT, HS, and 5-FU were purchased from Wako (Wako Ltd., Osaka, Japan). Cytotoxic activities against the human CCA cells CL-6 of the dual (BE:AT, BE:HS, and AT:HS) and triple (BE:AT:HS) combinations were evaluated using the assay. The cytotoxic interaction of each dual combination was assessed at five concentration ratios (10:0, 7:3, 5:5, 3:7, and 0:10) using isobologram analysis. The fractional inhibitory concentration index of each combination pair (representing combination scores) and the sum FIC of five distinctive ratios were calculated as the ratio of IC50 of the combination and that of each compound alone. For triple combination, the concentration ratio used in the experiment was 1:1.5:2.5(BE:AT:HS), and analysis of the interaction was performed using polygonogram analysis at the IC50 and IC90 concentrations (concentration that inhibits cell growth by 50% and 90%, respectively).

Results: The study was the first that confirmed the cytotoxic synergistic interaction of the three major compounds from AL rhizome on the human CCA cell line CL-6. The BE:AT combination produced the additive effect with a sum FIC (fractional inhibitory concentration) of 0.967±0.02 (mean±SD). The BE:HS and AT:HS combinations produced a synergistic effect with sum FICs of 0.685±0.08 and 0.767±0.09, respectively. The mixture of the three compounds produced synergistic interaction with CI (combination index) values of 0.519±0.10 and 0.65±0.17 (mean±SD) at the IC₅₀ and IC₉₀ concentration levels, respectively. 

Conclusion: The multi-ingredient characteristics of the plant extract would be expected to optimize therapy regarding both efficacy (synergistic anti-CCA activity) and tolerability (buffering effect). Results obtained would guide further development of AL as a potential anti-CCA chemotherapeutics concerning the appropriate pharmaceutical dosage form.

 

Author (s) Details

Pongsakorn Martviset
Center of Excellence in Molecular Biology and Pharmacology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Pathumthani 12121, Thailand and Faculty of Medical Technology, Rangsit University, Pathumthani 12000, Thailand.

 

Kesara Na-Bangchang
Center of Excellence in Molecular Biology and Pharmacology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Pathumthani 12121, Thailand, Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Pathumthani 12121, Thailand and Drug Discovery and Development Center, Thammasat University, Pathumthani 12121, Thailand.

 

Please see the book here:- https://doi.org/10.9734/bpi/crpbs/v3/2408

Inhibitory Effects of Atractylodin and β-eudesmol, the Major Constituents of Atractylodes lancea, on P-glycoprotein and Permeability Across Caco-2 Cells | Chapter 9 | Microbiology and Biotechnology Research: An Overview Vol. 4

 

 

Objectives: Atractylodin and β-eudesmol are the two active constituents of Atractylodes lancea (Thunb.) D.C. (AL), which has been demonstrated in a series of in vitro and in vivo studies for its potential activities against cholangiocarcinoma. The objective of the study was to investigate membrane permeability properties and effects on the efflux transporter P-glycoprotein (P-gp) using the Caco-2 cell line.

 

Methods: The Caco-2 cell monolayer's integrity was evaluated by measuring trans-epithelial electrical resistance (TEER) and permeation (P_app) of Lucifer yellow across the cell monolayer. The effects of atractylodin and β-eudesmol on P-gp were determined by measuring interference with the transport of the P-gp transport (Rhodamine 123: R123), and their modulatory effects on MDR-1 mRNA were detected using real-time polymerase chain reaction (RT-PCR).

 

Key Findings: The P_app values of atractylodin (50-200 µM) from apical to basolateral (A-B) and basolateral to apical (B-A) directions were 0.02-0.03×10-6 and 0.06-0.08×10-6 cm/sec, respectively, with the efflux ratios ranging from 2.5 to 2.9. The corresponding P_app values of β-eudesmol (50-200 µM) were 0.87-0.91×10-6 and 2.97-3.95×10-6 cm/sec, respectively, with the efflux ratios ranging from 3.24 to 4.63. Neither compounds were not inhibitors of P-gp and did not affect P-gp-mediated R123 transport across the Caco-2 cell monolayer. β-Eudesmol did not affect the function of P-glycoprotein and MDR-1 mRNA expression, while exposure to atractylodin at high concentration (320 µM) for 48 h induced P-gp at both gene and function levels.

 

Conclusions: Atractylodin and β-eudesmol exhibit low permeability across the Caco-2 cell monolayer in both directions, which is attributed to the efflux transport of both compounds into the cells. Inadequate concentrations of both compounds in the target cells may limit the clinical use of AL in patients with cholangiocarcinoma.

 

Author(s) Details

Artitaya Thiengsusuk
Graduate Studies, Chulabhorn International College of Medicine, Thammasat University, Pathum Thani 12120, Thailand.

 

Wiriyaporn Sumsakul
Thailand Institute of Scientific and Technological Research, Pathum Thani 12120, Thailand.

 

Kesara Na-Bangchang
Graduate Studies, Chulabhorn International College of Medicine, Thammasat University, Pathum Thani 12120, Thailand, Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Thammasat University, Pathum Thani 12120, Thailand and Drug Discovery and Development Center, Office of Advanced Science and Technology, Thammasat University, Pathum Thani 12120, Thailand.

 

Please see the book here:- https://doi.org/10.9734/bpi/mbrao/v4/5795

Synergistic Interactions of Atractylodes lancea Rhizome Compounds in the Treatment of Cholangiocarcinoma | Chapter 7 | Contemporary Research and Perspectives in Biological Science Vol. 3

Background: Cholangiocarcinoma (CCA)is the primary type of bile duct cancer with high morbidity and mortality, particularly in patients with advanced stages. Numerous studies have been carried out in efforts to discover effective cancer chemotherapeutic agents from plant sources with low toxicity. Treatment of CCA remains unsatisfactory due to the lack of sensitive and specific diagnostic tools for early detection and effective chemotherapeutics.

Purpose: The primary purpose of this study is to investigate cytotoxic interactions between the three major constituents of the rhizomes of Atractylodeslancea (Thunb)DC., i.e., β-eudesmol (BE), atractylodin (AT), and hinesol (HS) against CCA cell line. 

Methods: The bioactive constituents of AL rhizome under investigation, ie, BE, AT, HS, and 5-FU were purchased from Wako (Wako Ltd., Osaka, Japan). Cytotoxic activities against the human CCA cells CL-6 of the dual (BE:AT, BE:HS, and AT:HS) and triple (BE:AT:HS) combinations were evaluated using the assay. The cytotoxic interaction of each dual combination was assessed at five concentration ratios (10:0, 7:3, 5:5, 3:7, and 0:10) using isobologram analysis. The fractional inhibitory concentration index of each combination pair (representing combination scores) and the sum FIC of five distinctive ratios were calculated as the ratio of IC50 of the combination and that of each compound alone. For triple combination, the concentration ratio used in the experiment was 1:1.5:2.5(BE:AT:HS), and analysis of the interaction was performed using polygonogram analysis at the IC50 and IC90 concentrations (concentration that inhibits cell growth by 50% and 90%, respectively).

Results: The study was the first that confirmed the cytotoxic synergistic interaction of the three major compounds from AL rhizome on the human CCA cell line CL-6. The BE:AT combination produced the additive effect with a sum FIC (fractional inhibitory concentration) of 0.967±0.02 (mean±SD). The BE:HS and AT:HS combinations produced a synergistic effect with sum FICs of 0.685±0.08 and 0.767±0.09, respectively. The mixture of the three compounds produced synergistic interaction with CI (combination index) values of 0.519±0.10 and 0.65±0.17 (mean±SD) at the IC₅₀ and IC₉₀ concentration levels, respectively. 

Conclusion: The multi-ingredient characteristics of the plant extract would be expected to optimize therapy regarding both efficacy (synergistic anti-CCA activity) and tolerability (buffering effect). Results obtained would guide further development of AL as a potential anti-CCA chemotherapeutics concerning the appropriate pharmaceutical dosage form.

 

Author (s) Details

Pongsakorn Martviset
Center of Excellence in Molecular Biology and Pharmacology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Pathumthani 12121, Thailand and Faculty of Medical Technology, Rangsit University, Pathumthani 12000, Thailand.

 

Kesara Na-Bangchang
Center of Excellence in Molecular Biology and Pharmacology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Pathumthani 12121, Thailand, Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Pathumthani 12121, Thailand and Drug Discovery and Development Center, Thammasat University, Pathumthani 12121, Thailand.

 

Please see the book here:- https://doi.org/10.9734/bpi/crpbs/v3/2408

In-vitro and Ex-vivo Modulatory Effects of Atractylodin and β-Eudesmol on Human Cytochrome P450 Enzymes | Chapter 3 | Pharmaceutical Science: New Insights and Developments Vol. 1

Background: Atractylodin and β-eudesmol, the major bioactive compounds in Atractylodes lancea, are promising candidates for anti-cholangiocarcinoma. However, their modulatory effects on cytochrome P450s (CYP450s) remain unclear. 

Objective: This study aimed to investigate the modulatory effects of two bioactive compounds, atractylodin and β-eudesmol, derived from Atractylodes lancea, on human cytochrome P450 enzymes (CYP450s), both in vitro and ex vivo, to assess their potential risks in clinical applications, particularly for anti-cholangiocarcinoma therapy.

Methods: The inhibitory effects of atractylodin and β-eudesmol on recombinant human CYP450 enzymes (rCYP1A2, rCYP2C9, rCYP2C19, rCYP2D6, and rCYP3A4) were evaluated using luminogenic CYP450 kits. For the ex vivo analysis, mice were administered daily oral doses of atractylodin or β-eudesmol (100 mg/kg body weight) for 1, 7, 14, and 21 days. Liver samples were collected at each time point to assess mRNA and protein expression levels of CYP1A2 and CYP3A11 (the mouse equivalent of human CYP3A4) enzymes and their enzyme activities. 

Results: Both atractylodin and β-eudesmol showed weak inhibitory effects on all recombinant CYP450 enzymes compared with the reference inhibitors (IC50 values ranging from 167 µM to >686 µM). However, β-eudesmol was most potent against rCYP2C19 (IC₅₀ = 172.7 µM) and rCYP3A4 (IC50 = 218.6 µM). In the ex vivo study, short-term exposure (1-7 days) to these compounds led to upregulating CYP1A2 and CYP3a11 mRNA, protein expression, and enzyme activity. In contrast, prolonged exposure (≥14 days) resulted in significant downregulation of these markers, which correlated with decreased enzyme activities, particularly CYP1A2 and CYP3a11.

Clinical Implications: These findings highlight potential clinical concerns for using atractylodin and β-eudesmol in treating cholangiocarcinoma, especially with prolonged dosing. Chronic exposure to these compounds may inhibit CYP3A4 activity, leading to potential toxicity and metabolic interactions with coadministered drugs that rely on CYP3A4 for metabolism. Caution is advised when using these compounds in combination therapies.

Conclusion: While atractylodin and β-eudesmol show promise as anti-cholangiocarcinoma agents, their chronic use may pose risks due to CYP3A4 inhibition and potential drug interactions. Further studies are needed to evaluate their safety profile and therapeutic window in clinical settings.

 

Author (s) Details

 

Artitaya Thiengsusuk
Chulabhorn International College of Medicine, Thammasat University, Pathumthani 12120, Thailand.

 

Tullayakorn Plengsuriyakarn
Chulabhorn International College of Medicine, Thammasat University, Pathumthani 12120, Thailand and Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Thammasat University, Pathumthani 12120, Thailand.

 

Kesara Na-Bangchang
Chulabhorn International College of Medicine, Thammasat University, Pathumthani 12120, Thailand, Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Thammasat University, Pathumthani 12120, Thailand and Drug Discovery and Development Center, Office of Advanced Science and Technology, Thammasat University, Pathumthani 12120, Thailand.

 

Please see the book here:- https://doi.org/10.9734/bpi/psnid/v1/3509

Immunomodulatory Activities of Atractylodes lancea (Thunb.) DC | Chapter 5 | Current Practice in Medical Science Vol. 7

 

 In vitro and In vivo research have shown that Atractylodes lancea (Thunb) DC. (AL) and its bioactive parts - eudesmol and atractylodin could be utilized to treat cholangiocarcinoma. The review meant to assess the immunomodulatory action of AL in human subjects. The modulatory impacts of AL and -eudesmol and atractylodin on TNFα and IL6 articulation in PBMCs were estimated utilizing continuous PCR. Blood tests were taken from 48 sound subjects after they were given a solitary or various dosages of the normalized AL remove case definition or a fake treatment. Serum cytokine profiles, lymphocyte subpopulations (B lymphocytes, CD8+ cytotoxic T lymphocytes, CD4+ T-partner lymphocytes, and NK cells), and cytotoxic action of PBMCs against the cholangiocarcinoma cell line CL-6 were assessed utilizing cytometric dab exhibit (CBA) with stream cytometry examination. AL separate at practically all focuses essentially hindered both TNFα and IL6 articulation in Con A-interceded irritation in PBMCs. Just IL6 articulation was altogether decreased by β-Eudesmol at all dosages. At the most reduced portion, atractylodin impressively diminished the statement of the two cytokines, though at the most elevated fixation, just IL6 articulation was altogether restrained. The organization of AL at a solitary oral portion of 1,000 mg seemed to diminish IFN and IL10 and increment B cells, while fundamentally expanding NK and CD4+ and CD8+ cells. At 24 hours after measurements, there was a pattern of expanding cytotoxic action of PBMCs (comparative with fake treatment). At 24 hours after measurement, AL at progressive portions of 1,000 mg for 21 days would in general decrease the creation of all cytokines while fundamentally stifling IL17A creation. By 24 hours, there was a pattern of expanded cytotoxic action in PBMCs, yet this pattern halted at 48 hours. The discoveries support AL's immunomodulatory properties in people. This action, along with AL's immediate impact in setting off apoptosis in cholangiocarcinoma cells, suggests that it could play a part in CCA guideline.

Author(s) Details:

Inthuon Kulma,
Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathumthani 12121, Thailand and Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Thammasat University (Rangsit Campus), Pathumthani 12121, Thailand.

Luxsana Panrit,
Drug Discovery and Development Center, Office of Advanced Science and Technology, Thammasat University (Rangsit Campus), Pathumthani 12121, Thailand.

Tullayakorn Plengsuriyakarn,
Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathumthani 12121, Thailand and Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Thammasat University (Rangsit Campus), Pathumthani 12121, Thailand.

Wanna Chaijaroenkul,
Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathumthani 12121, Thailand and Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Thammasat University (Rangsit Campus), Pathumthani 12121, Thailand.

Siriprapa Warathumpitak,
Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathumthani 12121, Thailand and  Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Thammasat University (Rangsit Campus), Pathumthani 12121, Thailand.

Kesara Na-Bangchang,
Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathumthani 12121, Thailand and Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Thammasat University (Rangsit Campus), Pathumthani 12121, Thailand and  Drug Discovery and Development Center, Office of Advanced Science and Technology, Thammasat University (Rangsit Campus), Pathumthani 12121, Thailand.

Please see the link here: https://stm.bookpi.org/CPMS-V7/article/view/7836