Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells

Gu, Ha Ra; Park, Su Cheol; Choi, Su Jin; Lee, Jae Cheol; Kim, You Cheoul; Han, Chul Ju; Kim, Jin; Yang, Ki Young; Kim, Yeon Joo; Noh, Geum Youb; No, So Hyeon; Jeong, Jae Hoon

doi:10.3350/cmh.2015.21.1.49

Cited by 38 publications

(27 citation statements)

References 43 publications

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“…A study conducted by Gu and coworkers reported that silibinin in combination with sorafenib/gefitinib inhibits growth of cancerous cell lines, but their work mainly emphasize on the efficacy of silibinin-gefitinib combination. [25]. Our result strengthens the idea that sorafenib in combination with silibinin have synergestic effect on HCC cell line.…”

Section: Discussionsupporting

confidence: 86%

Sustained Release Tablets of Sorafenib-Silibinin Combinations for the Treatment of Hepatocellular Carcinoma

et al. 2018

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Objective: The aim of this study was to develop polymer coated sustained release tablet using sorafenib and silibinin combination for the treatment of hepatocellular carcinoma.Methods: The qualitative analysis such as weight variation, friability, hardness, interaction studies, disintegration and in vitro release were performed to validate formulated tablets. We have maintained the acceptable official limits for weight variation, friability, hardness and disintegration time according to prescribed pharmacopoeial recommendation. In vitro drug release studies were performed using USP-II (paddle type) dissolution apparatus. The MTT assay was performed for assessment of Cell viability of drug combination for tablet formulation. Molecular docking studies have been performed to determine the combinatorial mode of action for the tablet formulation.Results: Friability and weight variation were less than 1% for each formulation, which were within range of prescribed pharmacopoeial recommendation. The hardness of 20 tablets showed 5-6.5Kg/cm2 for all formulations 5-6.5Kg/cm2. The optimized formulation resulted in 98% drug release after 28 h. The present study reports the synergistic effects of drug combination to inhibit cell growth in HepG2 cell line. Molecular docking studies showed that sorafenib has high binding affinity for B-Raf vascular endothelial growth factor receptor β and protein kinase B. Silibinin showed binding affinity with MAP kinase-11, protein phosphatase 2 A and tankyrase.Conclusion: The present study reports for the first time a novel formulation for sustained release and reduced toxicity of sorafenib with enhanced inhibitory effect of the drug combination on cancerous hepatic cell line as well collaborative mechanism of action for the formulation.

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Section: Discussionsupporting

confidence: 86%

Sustained Release Tablets of Sorafenib-Silibinin Combinations for the Treatment of Hepatocellular Carcinoma

et al. 2018

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“…Silibinin, a polyphenolic flavonoid component isolated from the fruits or seeds of milk thistle (Silybum marianum), has been clinically used to treat various diseases, and it has been suggested that this reagent exhibited protective effects for patients with liver or heart disease. The inhibitory effects of silibinin against cancer were also indicated (11)(12)(13)(14)(15)(16)(17) in tumors such as breast cancer and head and neck squamous cell carcinomas. Our previous study indicated that silibinin inhibited BCa progression (18), leading us to hypothesize a link between silibinin and BCa chemoresistance.…”

Section: Introductionmentioning

confidence: 97%

Silibinin suppresses bladder cancer cell malignancy and chemoresistance in an NF-κB signal-dependent and signal-independent manner

Sun

Guan

Zhao

et al. 2017

International Journal of Oncology

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Because bladder cancer (BCa) is the 9th most common malignant tumor and 13th leading cause of death due to cancer, therapeutic approaches have attracted a great deal of attention from both clinicians and BCa patients. Although the development of surgery and targeted drugs has brought new challenges for the traditional concept of BCa therapy, various types of chemotherapy remain the final treatment method for many BCa patients. However, chemoresistance inevitably appears, leading to the failure of chemotherapy. Silibinin, a polyphenolic flavonoid component isolated from the fruits or seeds of milk thistle, has been reported to play important roles in inhibiting tumor chemoresistance in breast cancer and head and neck squamous cell carcinomas. Our previous study indicated that silibinin inhibited BCa progression in some mechanisms but with no conclusion of chemoresistance inhibition. Therefore, in the present study, we dissected the role of silibinin in BCa progression and chemoresistance. Our results revealed that in BCa, chemodrug-induced chemoresistance was reversed in the presence of silibinin. Further mechanistic study indicated that silibinin suppressed chemoresistance and BCa malignancy in an NF-κB-dependent and -independent manner. In addition, all of the inhibitory effects were dose‑dependent. Thus, our results provide a potential use for silibinin in BCa therapeutics.

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“…Further, silibinin induced autophagy in human fibrosarcoma HT1080 cells by activation of the p53 by ROS/p38/JNK pathway [170] in melanoma A375-S2 cells [171] and human colon cancer cells SW480 and SW620 [172]. However, silibinin exerted its anticancer effect via the apoptotic pathway in HCC cells, such as Huh7, HepG2, Huh-BAT, Hep3B, HepG2, PLC/PRF5, SNU387, SNU398, SNU449, SNU475, and SNU761cells, and also exhibited growth-inhibitory activity with either sorafenib or gefitinib via a synergistic manner in the SNU761 cell line [173]. Since silibinin is an effective inducer of autophagy in various cell lines, its role as an autophagy-mediated anti-HCC effect needs to be explored further.…”

Section: Polyphenols As Modulators Of Autophagy In Cancermentioning

confidence: 99%

Autophagy: A Potential Therapeutic Target of Polyphenols in Hepatocellular Carcinoma

Kiruthiga

Devi

Nabavi

et al. 2020

Cancers

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Autophagy is a conserved biological phenomenon that maintains cellular homeostasis through the clearing of damaged cellular components under cellular stress and offers the cell building blocks for cellular survival. Aberrations in autophagy subsidize to various human pathologies, such as dementia, cardiovascular diseases, leishmaniosis, influenza, hepatic diseases, and cancer, including hepatocellular carcinoma (HCC). HCC is the fifth common mortal type of liver cancer globally, with an inhomogeneous topographical distribution and highest incidence tripled in men than women. Existing treatment procedures with liver cancer patients result in variable success rates and poor prognosis due to their drug resistance and toxicity. One of the pathophysiological mechanisms that are targeted during the development of anti-liver cancer drugs is autophagy. Generally, overactivated autophagy may lead to a non-apoptotic form of programmed cell death (PCD) or autophagic cell death or type II PCD. Emerging evidence suggests that manipulation of autophagy could induce type II PCD in cancer cells, acting as a potential tumor suppressor. Hence, altering autophagic signaling offers new hope for the development of novel drugs for the therapy of resistant cancer cells. Natural polyphenolic compounds, including flavonoids and non-flavonoids, execute their anticarcinogenic mechanism through upregulating tumor suppressors and autophagy by modulating canonical (Beclin-1-dependent) and non-canonical (Beclin-1-independent) signaling pathways. Additionally, there is evidence signifying that plant polyphenols target angiogenesis and metastasis in HCC via interference with multiple intracellular signals and decrease the risk against HCC. The current review offers a comprehensive understanding of how natural polyphenolic compounds exhibit their anti-HCC effects through regulation of autophagy, the non-apoptotic mode of cell death.

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Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells

Cited by 38 publications

References 43 publications

Sustained Release Tablets of Sorafenib-Silibinin Combinations for the Treatment of Hepatocellular Carcinoma

Sustained Release Tablets of Sorafenib-Silibinin Combinations for the Treatment of Hepatocellular Carcinoma

Silibinin suppresses bladder cancer cell malignancy and chemoresistance in an NF-κB signal-dependent and signal-independent manner

Autophagy: A Potential Therapeutic Target of Polyphenols in Hepatocellular Carcinoma

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