Asiatic acid induces endoplasmic reticulum stress and apoptotic death in glioblastoma multiforme cells both in vitro and in vivo

Kavitha, C.; Jain, Anil K.; Agarwal, Chapla; Pierce, Angela; Keating, Amy K.; Huber, Kendra M.; Serkova, Natalie J.; Wempe, Michael F.; Agarwal, Rajesh; Deep, Gagan

doi:10.1002/mc.22220

Cited by 40 publications

(36 citation statements)

References 42 publications

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“…In recent studies, molecular targets involved in apoptotic processes have created an opportunity to develop more effective drugs for cancer. In this regard, UPR-signaling pathway is an interesting area of investigations (6,9,16). Although relationships of Bv and different cellular apoptotic pathways have been described, UPR activation has been uncovered as an important mechanism of Bv impact on various tumor cell lines (13).…”

Section: Discussionmentioning

confidence: 99%

Bee Venom Induces Unfolded Protein Response in A172 Glioblastoma Cell Line

Bazi¹,

Gholamin²,

Sisakht³

et al. 2015

Biotech Health Sci

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Background: Glioblastoma is a type of brain tumor with poor response to available therapies, and shows high rate of mortality. Despite remarkable advancements in our knowledge about cytogenetic and pathophysiologic features of glioblastoma, current treatment strategies are mainly based on cytotoxic drugs; however, these therapeutic approaches are facing progressive failure because of the resistant nature of glioblastomas. In the recent years, however, promising results have emerged owing to targeted therapies toward molecular pathways within cancerous cells. Unfolded Protein Response (UPR) is a remarkable signaling pathway that triggers both apoptosis and survival pathways within cells, and therefore induces UPR-related apoptotic pathways in cancer cells by ER stress inducers. Objectives: Recently, the role of Bee venom (Bv), which contains powerful bioactive peptides, in inducing UPR-related apoptosis was revealed in cancer cell lines. Nevertheless, currently there are no reports of Bv potential ability in induction of UPR apoptotic routes in glioblastoma. The aim of current study was to evaluate possible role of Bee venome in inducing of UPR pathway within A172 glioblastoma cell line. Materials and Methods: We treated the A172 glioblastoma cell line with different Bv doses, and assessed UPR-related genes expression by real-time Polymerase Chain Reaction (PCR). Results: The IC50 of Bv for the studied cell line was 28 μg/mL. Furthermore, we observed that Bv can induce UPR target genes (Grp94 and Gadd153) over-expression through a dose-dependent mechanism. Conclusions: Our results suggest the potential role of Bv as a therapeutic agent for glioblastomas.

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Section: Discussionmentioning

confidence: 99%

Bee Venom Induces Unfolded Protein Response in A172 Glioblastoma Cell Line

Bazi¹,

Gholamin²,

Sisakht³

et al. 2015

Biotech Health Sci

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“…Recently, several studies have demonstrated the pro-apoptotic and cell growth inhibitory activity of AA in the liver, breast, skin, brain, and gastrointestinal tumor cells (Lee et al, 2002 ; Hsu et al, 2005 ; Park et al, 2005 ; Cho et al, 2006 ; Tang et al, 2009 ; Kavitha et al, 2015 ; Wu et al, 2015 ). AA treatment was found to attenuate inflammation, tumor cell proliferation, and induce mitochondrial pathway of apoptosis.…”

Section: Asiatic Acid In Cancermentioning

confidence: 99%

Pharmacological Properties, Molecular Mechanisms, and Pharmaceutical Development of Asiatic Acid: A Pentacyclic Triterpenoid of Therapeutic Promise

et al. 2018

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Asiatic acid (AA) is a naturally occurring aglycone of ursane type pentacyclic triterpenoids. It is abundantly present in many edible and medicinal plants including Centella asiatica that is a reputed herb in many traditional medicine formulations for wound healing and neuropsychiatric diseases. AA possesses numerous pharmacological activities such as antioxidant and anti-inflammatory and regulates apoptosis that attributes its therapeutic effects in numerous diseases. AA showed potent antihypertensive, nootropic, neuroprotective, cardioprotective, antimicrobial, and antitumor activities in preclinical studies. In various in vitro and in vivo studies, AA found to affect many enzymes, receptors, growth factors, transcription factors, apoptotic proteins, and cell signaling cascades. This review aims to represent the available reports on therapeutic potential and the underlying pharmacological and molecular mechanisms of AA. The review also also discusses the challenges and prospects on the pharmaceutical development of AA such as pharmacokinetics, physicochemical properties, analysis and structural modifications, and drug delivery. AA showed favorable pharmacokinetics and found bioavailable following oral or interaperitoneal administration. The studies demonstrate the polypharmacological properties, therapeutic potential and molecular mechanisms of AA in numerous diseases. Taken together the evidences from available studies, AA appears one of the important multitargeted polypharmacological agents of natural origin for further pharmaceutical development and clinical application. Provided the favorable pharmacokinetics, safety, and efficacy, AA can be a promising agent or adjuvant along with currently used modern medicines with a pharmacological basis of its use in therapeutics.

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“…Natural products are emerging as an important source of new potential candidates for the treatment or as adjuvant therapy for glioblastoma (41)(42)(43)(44). In GBM, natural triterpenes were shown to induce cell arrest and/or apoptosis both in vitro (45,46) and in vivo (47), to inhibit migration and invasion (48) and to attenuate TMz resistance (49). Results presented in this study show that the pentacyclic triterpene pomolic acid (PA) is cytotoxic to GBM cell lines and that this effect is associated with induction of apoptosis, uncoupling of mitochondria potential, increase in ROS production and modulation of MDR pump, MRP1/ABCC1 activity.…”

Section: Malignant Central Nervous System Neoplasms Particularlymentioning

confidence: 99%

Pomolic acid induces apoptosis and inhibits multidrug resistance protein MRP1 and migration in glioblastoma cells

et al. 2017

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Glioblastoma (GBM), the most aggressive of primary brain tumors, determine short survival and poor quality of life. Therapies used for its treatment are not effective and chemotherapy failure is partially due to multidrug resistance (MDR) mechanisms present in the tumor cells. New therapeutic strategies are needed in order to improve survival in GBM. The present study investigated the activity of the pentacyclic triterpene pomolic acid (PA) in GBM. Pomolic acid decreased the viability and induced apoptosis of GBM cells as demonstrated by DNA fragmentation. It also induced uncoupling of mitochondria membrane potential and activation of caspase-3 and -9. Pomolic acid-induced apoptosis is dependent on reactive oxygen species (ROS) production as it is inhibited by anti-oxidant treatment. Pomolic acid also down-modulated the activity of the multidrug resistance associated protein 1 (MRP1) and inhibited migration of GBM cells. These results show that PA acts on several pathways of GBM drug resistance and therefore may be of potential interest for the treatment of this tumor.

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Asiatic acid induces endoplasmic reticulum stress and apoptotic death in glioblastoma multiforme cells both in vitro and in vivo

Cited by 40 publications

References 42 publications

Bee Venom Induces Unfolded Protein Response in A172 Glioblastoma Cell Line

Bee Venom Induces Unfolded Protein Response in A172 Glioblastoma Cell Line

Pharmacological Properties, Molecular Mechanisms, and Pharmaceutical Development of Asiatic Acid: A Pentacyclic Triterpenoid of Therapeutic Promise

Pomolic acid induces apoptosis and inhibits multidrug resistance protein MRP1 and migration in glioblastoma cells

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