Synergistic potential of dual andrographolide and melatonin targeting of metastatic colon cancer cells: Using the Chou-Talalay combination index method

Banerjee, Vivekjyoti; Sharda, Neha; Huse, Jared; Singh, Damandeep; Sokolov, Daniil; Czinn, Steven J.; Blanchard, Thomas G.; Banerjee, Aditi

doi:10.1016/j.ejphar.2021.173919

Cited by 37 publications

(41 citation statements)

References 70 publications

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“…The MTT assays revealed that HCT116 cells treated with both compounds exhibited greater growth inhibition (Figure 7 A). Compusyn was used to calculate the combination index (CI) values of erastin/tagitinin C cotreatments in HCT116 cells, the CI value was 0.72662 when tagitinin C (10 µM) and erastin (20 µM) was used, which meant moderate synergism 48 . When used alone, erastin had no significant inhibitory effect on the proliferation of HCT116 cells.…”

Section: Resultsmentioning

confidence: 99%

Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells

Wei¹,

Zhao²,

Wang³

et al. 2021

Int. J. Biol. Sci.

246

102

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Rationale: Colorectal cancer (CRC) is a common malignant tumor of the digestive system. However, the efficacy of surgery and chemotherapy is limited. Ferroptosis is an iron-and reactive oxygen species (ROS)-dependent form of regulated cell death (RCD) and plays a vital role in tumor suppression. Ferroptosis inducing agents have been studied extensively as a novel promising way to fight against therapy resistant cancers. The aim of this study is to investigate the mechanism of action of tagitinin C (TC), a natural product, as a novel ferroptosis inducer in tumor suppression. Methods: The response of CRC cells to tagitinin C was assessed by cell viability assay, clonogenic assay, transwell migration assay, cell cycle assay and apoptosis assay. Molecular approaches including Western blot, RNA sequencing, quantitative real-time PCR and immunofluorescence were employed as well. Results: Tagitinin C, a sesquiterpene lactone isolated from Tithonia diversifolia, inhibits the growth of colorectal cancer cells including HCT116 cells, and induced an oxidative cellular microenvironment resulting in ferroptosis of HCT116 cells. Tagitinin C-induced ferroptosis was accompanied with the attenuation of glutathione (GSH) levels and increased in lipid peroxidation. Mechanistically, tagitinin C induced endoplasmic reticulum (ER) stress and oxidative stress, thus activating nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). As a downstream gene (effector) of Nrf2, heme oxygenase-1 (HO-1) expression increased significantly with the treatment of tagitinin C. Upregulated HO-1 led to the increase in the labile iron pool, which promoted lipid peroxidation, meanwhile tagitinin C showed synergistic anti-tumor effect together with erastin. Conclusion:In summary, we provided the evidence that tagitinin C induces ferroptosis in colorectal cancer cells and has synergistic effect together with erastin. Mechanistically, tagitinin C induces ferroptosis through ER stress-mediated activation of PERK-Nrf2-HO-1 signaling pathway. Tagitinin C, identified as a novel ferroptosis inducer, may be effective chemosensitizer that can expand the efficacy and range of chemotherapeutic agents.

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Section: Resultsmentioning

confidence: 99%

Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells

Wei¹,

Zhao²,

Wang³

et al. 2021

Int. J. Biol. Sci.

246

102

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“…Given that the toxicity and side effects has been acknowledged with the vast majority of chemotherapeutic agents, in the past few decades, researchers have paid increasing attention to the anticancer investigation of natural active ingredients, especially andrographolide (Islam et al, 2018; Malik et al, 2021; Soo et al, 2019). Published projects have validated the multiple anticancer effects, such as its ability to colon cancer (Banerjee et al, 2021; Vukmirovic, Vo, Seymour, Rollo, & Mothersill, 2021), lung cancer (Luo et al, 2021), cervical cancer (Pasha et al, 2021), breast cancer (Wanandi et al, 2020), hepatoma cancer (Shi, Zhang, Zheng, Lu, & Ji, 2017) as well as renal carcinoma (Bi et al, 2020) and so on, which the cytotoxic effects on these cancer cells above were bound up with inhibiting proliferation (Khan, Mahfooz, & Ansari, 2020), migration and invasion (Pearngam, Kumkate, Okada, & Janvilisri, 2019), blocking cell cycle (Khan, Mahfooz, Faisal, Alatar, & Ansari, 2020), inducing apoptosis (Wang et al, 2020), restraining tumor angiogenesis (Kajal et al, 2019), as well as enhancing chemosensitivity (Li et al, 2020; Mao, He, Wang, Wu, & Wei, 2019). The main anticancer mechanisms of andrographolide are depicted in Figure 4.…”

Section: Pharmacologymentioning

confidence: 99%

Andrographolide: A review of its pharmacology, pharmacokinetics, toxicity and clinical trials and pharmaceutical researches

Zeng

Wei

Zhou

et al. 2021

Phytotherapy Research

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Andrographis paniculata (Burm. f.) Wall. ex Nees, a renowned herb medicine in China, is broadly utilized in traditional Chinese medicine (TCM) for the treatment of cold and fever, sore throat, sore tongue, snake bite with its excellent functions of clearing heat and toxin, cooling blood and detumescence from times immemorial. Modern pharmacological research corroborates that andrographolide, the major ingredient in this traditional herb, is the fundamental material basis for its efficacy. As the main component of Andrographis paniculata (Burm. f.) Wall. ex Nees, andrographolide reveals numerous therapeutic actions, such as antiinflammatory, antioxidant, anticancer, antimicrobial, antihyperglycemic and so on. However, there are scarcely systematic summaries on the specific mechanism of disease treatment and pharmacokinetics. Moreover, it is also found that it possesses easily ignored security issues in clinical application, such as nephrotoxicity and reproductive toxicity. Thereby it should be kept a lookout over in clinical. Besides, the relationship between the efficacy and security issues of andrographolide should be investigated and evaluated scientifically. In this review, special emphasis is given to andrographolide, a multifunctional natural terpenoids, including its pharmacology, pharmacokinetics, toxicity and pharmaceutical researches. A brief overview of its clinical trials is also presented. This review intends to systematically and comprehensively summarize the current researches of andrographolide, which is of great significance for the development of andrographolide clinical products. Noteworthy, those un‐cracked issues such as specific pharmacological mechanisms, security issues, as well as the bottleneck in clinical transformation, which detailed exploration and excavation are still not to be ignored before achieving integration into clinical practice. In addition, given that current extensive clinical data do not have sufficient rigor and documented details, more high‐quality investigations in this field are needed to validate the efficacy and/or safety of many herbal products.

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“… 32 Additional study provided the evidence for its possible clinical application in enhancing the antitumor effect. 33 Recently, it is reported the synergistic cytotoxicity of AGP and MLT in mCRC cell lines, colospheroids and 5-FU drug resistance cells 34 and the molecular mechanism is apoptosis due to UPR-mediated ER stress and angiogenic inhibition. In this study, we have used a combination of AGP and MLT for metastatic CRC cell inhibition as both compounds have antiangiogenic, apoptotic, cell cycle arrest dysregulation of various cancer signaling pathways and involved in regulation of immune function and tumor microenvironments.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we have used a combination of AGP and MLT for metastatic CRC cell inhibition as both compounds have antiangiogenic, apoptotic, cell cycle arrest dysregulation of various cancer signaling pathways and involved in regulation of immune function and tumor microenvironments. 34 Here, we examined the uses of a lower concentration of AGP when administered in combination with MLT (0.5 mM). The therapeutic concentration of MLT (0.5 mM) was selected because it modulates several signaling pathways which are considered likely antimetastasis, antiproliferative, and pro-apoptotic pathways in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Impact of Andrographolide and Melatonin Combinatorial Drug Therapy on Metastatic Colon Cancer Cells and Organoids

Sharda

Ikuse

Hill

et al. 2021

Clin Med Insights Oncol

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Background: The death rate (the number of deaths per 100 000 people per year) of colorectal cancer (CRC) has been dropping since 1980 due to increased screening, lifestyle-related risk factors, and improved treatment options; however, CRC is the third leading cause of cancer-related deaths in men and women in the United States. Therefore, successful therapy for CRC is an unmet clinical need. This study aimed to investigate the impacts of andrographolide (AGP) and melatonin (MLT) on CRC and the underlying mechanism. Methods: To investigate AGP and MLT anticancer effects, a series of metastatic colon cancer cell lines (T84, Colo 205, HT-29, and DLD-1) were selected. In addition, a metastatic patient-derived organoid model (PDOD) was used to monitor the anticancer effects of AGP and MLT. A series of bioassays including 3D organoid cell culture, MTT, colony formation, western blotting, immunofluorescence, and quantitative polymerase chain reaction (qPCR) were performed. Results: The dual therapy significantly promotes CRC cell death, as compared with the normal cells. It also limits CRC colony formation and disrupts the PDOD membrane integrity along with decreased Ki-67 expression. A significantly higher cleaved caspase-3 and the endoplasmic reticulum (ER) stress proteins, IRE-1 and ATF-6 expression, by 48 hours were found. This combinatorial treatment increased reactive oxygen species (ROS) levels. Apoptosis signaling molecules BAX, XBP-1, and CHOP were significantly increased as determined by qPCR. Conclusions: These findings indicated that AGP and MLT associated ER stress-mediated apoptotic metastatic colorectal cancer (mCRC) cell death through the IRE-1/XBP-1/CHOP signaling pathway. This novel combination could be a potential therapeutic strategy for mCRC cells.

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Synergistic potential of dual andrographolide and melatonin targeting of metastatic colon cancer cells: Using the Chou-Talalay combination index method

Cited by 37 publications

References 70 publications

Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells

Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells

Andrographolide: A review of its pharmacology, pharmacokinetics, toxicity and clinical trials and pharmaceutical researches

Impact of Andrographolide and Melatonin Combinatorial Drug Therapy on Metastatic Colon Cancer Cells and Organoids

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