Withaferin A (WFA) inhibits tumor growth and metastasis by targeting ovarian cancer stem cells

Kakar, Sham S.; Parte, Seema; Carter, Kelsey; Joshua, Irving G.; Worth, Christopher A.; Rameshwar, Pranela; Ratajczak, Mariusz Z.

doi:10.18632/oncotarget.20170

Cited by 39 publications

(35 citation statements)

References 63 publications

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“…Withaferin A (WFA) is a steroidal lactone that has been validated as an anticancer agent in a range of murine tumor models, including breast, prostate, and ovarian cancer (31–33). WFA causes vimentin aggregation in cells by promoting phosphorylation at serine 38 (Ser38) and serine 56 (Ser56) (34).…”

Section: Resultsmentioning

confidence: 99%

Vimentin is Required for Tumor Progression and Metastasis in a Mouse Model of Non-Small Cell Lung Cancer

Berr¹,

Wiese²,

Santos³

et al. 2020

Preprint

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1Vimentin, a type III intermediate filament, is highly expressed in aggressive epithelial 2 cancers and is associated with increased rates of metastasis. We show that vimentin is causally 3 required for lung cancer metastasis using a genetic mouse model of lung adenocarcinoma (LSL-4 Kras G12D ;Tp53 fl/fl , termed KPV +/+ ) crossed with vimentin-null mice (thereby creating KPV −/− mice). 5Both KPV +/+ and KPV −/− mice developed lung tumors, yet KPV −/− mice had delayed tumorigenesis 6 and prolonged survival. KPV +/+ cells implanted in the flank metastasized to the lung while KPV −/− 7 cells did not, providing additional evidence that vimentin is required for metastasis. Differential 8 expression analysis of RNA-seq data demonstrated that KPV −/− cells had suppressed expression 9 of genes that drive epithelial-to-mesenchymal transition, migration, and invasion, processes that 10 are critical to the metastatic cascade. Integrative metabolomic and transcriptomic analysis 11 revealed altered glutaminolysis, with KPV −/− cells accumulating glutathione, leading to impaired 12 cell motility in response to oxidative stress. Together, these results show that loss of vimentin 13 impairs epithelial-to-mesenchymal transition and regulation of the oxidative stress response, 14 resulting in decreased metastasis in murine lung adenocarcinoma. 15 16 17 18Non-small-cell lung cancers (NSCLCs) represent 80% of all lung cancers and are often 20 diagnosed at more advanced stages of the disease resulting in high rates of mortality (1). 21Adenocarcinoma is the most common subtype of NSCLC and is characterized by activating 22 mutations in the Kras proto-oncogene in up to 30% of diagnoses and by inactivating mutations in 23 the tumor suppressor gene Tp53 in up to 60% of diagnoses (2)(3)(4)(5). Despite the prevalence of lung 24 adenocarcinoma, the metastatic mechanisms that drive lung cancer progression are incompletely 25 understood. 26The type III intermediate filament vimentin is associated with increased metastatic spread 27 and lower rates of survival in patients with NSCLC (6-8). Vimentin is a canonical marker of 28 epithelial-to-mesenchymal transition (EMT), an initiating event of the metastatic cascade (9). EMT 29 is the process by which epithelial cells remodel cell-cell and cell-extracellular-matrix (ECM) 30 contacts, lose their apical-basal polarity, and adopt the spindle-shaped morphology associated 31 with a mesenchymal cell phenotype (10). During EMT, cells undergo a downregulation of 32 epithelial cell associated genes, including E-cadherin and cytokeratins, and an upregulation of 33 mesenchymal cell associated genes, including N-cadherin and vimentin. In addition to acting as 34 a marker of EMT, vimentin is functionally involved in EMT. Structurally, vimentin intermediate 35 filaments control cell shape, and thus facilitate the transition toward a mesenchymal phenotype 36(11). Twist1, a transcription factor critical to EMT, upregulates vimentin expression (12). Vimentin 37 also serves as a scaffold for Slug, another transc...

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Section: Resultsmentioning

confidence: 99%

Vimentin is Required for Tumor Progression and Metastasis in a Mouse Model of Non-Small Cell Lung Cancer

Berr¹,

Wiese²,

Santos³

et al. 2020

Preprint

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“…Withaferin A (WFA) is a steroidal lactone isolated from the plant Withania somnifera, also known as Ashwagandha [24]. It is known for its anti-in ammatory properties, as well as its anti-tumorigenic properties [25][26][27]. Recent work has demonstrated that COVID-19 infections have a large immune component and can result in the development of cytokine storm, a potentially life-threatening immune reaction in which the body release too many cytokines into the blood at a rapid rate [28].…”

Section: Withaferin a As A Prospective Treatmentmentioning

confidence: 99%

Withaferin A: a potential therapeutic agent against COVID-19 infection

Straughn

Kakar

2020

Preprint

Self Cite

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The outbreak and continued spread of the novel coronavirus disease 2019 (COVID-19) is a preeminent global health threat that has resulted in the infection of over 6 million people worldwide. In addition, the pandemic has claimed the lives of over 350,000 people worldwide. Age and the presence of underlying comorbid conditions have been found to be key determinants of patient mortality. One such comorbidity is the presence of an oncological malignancy, with cancer patients exhibiting an approximate two-fold increase in mortality rate. Due to a lack of data, no consensus has been reached about the best practices for the diagnosis and treatment of cancer patients. Interestingly, two independent research groups have discovered that Withaferin A (WFA), a steroidal lactone with anti-inflammatory and anti-tumorigenic properties, may bind to the viral spike (S-) protein of SARS-CoV-2. Further, preliminary data from our research group has demonstrated that WFA does not alter expression of ACE2 in the lungs of tumor-bearing female mice. Downregulation of ACE2 has recently been demonstrated to increase the severity of COVID-19. Therefore, WFA demonstrates real potential as a therapeutic agent to treat or prevent the spread of COVID-19 due to the reported interference in viral S-protein to host receptor binding and its lack of effect on ACE2 expression in the lungs.

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“…Withaferin A (WFA) merupakan komponen bioaktif dari tumbuhan Withania somnifera yang memiliki efek luas pada kanker ovarium. 11,22,[27][28][29][30][31] Dalam proses karsinogenesis kanker ovarium, nerve growth factor (NGF) yang merupakan molekul polipeptida kecil memiliki peran dalam proses proliferasi dan migrasi. Afinitas yang tinggi dimiliki oleh NGF terhadap reseptor tyrosine kinase A (TRKA) dan banyak terekspresikan pada kanker ovarium selain bentuk aktifnya berupa p-TRKA.…”

Section: Pegylated Liposom Pada Kanker Ovariumunclassified

“…33 WFA juga mampu menghambat proliferasi dengan mekanisme yang berbeda, mencegah metastasis, mencegah kekambuhan (relaps) dan kemoresisten dengan mengeliminasi cancer stem cell (CSC). 29 Penjelasan terkait kekambuhan pada kanker ovarium, erat kaitannya dengan pembawaan sifat resisten dan interaksi dengan tumor microenvironment. [35][36][37] Metastasis diinisiasi oleh CSC yang berdiferensiasi menjadi ovarian cancer stem cell (ovarian CSC) dan memroduksi Growth-regulated oncogene 1 (GRO-1) sehingga menginisiasi transformasi fibroblast menjadi senescent fibroblast.…”

Section: Review Articleunclassified

“…Spheroid merupakan agregat tumor ganas yang berfungsi untuk mengevaluasi kemampuan CSC untuk bermetastasis secara in vitro. 29,72 Spheroid dalam kanker ovarium berfungsi sebagai kendaraan untuk penyebaran sel kanker di rongga peritoneum, melindungi sel dari anoikis dan menghambat akses agen kemoterapi seperti cisplatin menuju sel kanker. 73,74 Penghambatan jalur persinyalan β-catenin akan menganggu pembentukan agregat multiseluler (spheroid) dan menghambat metastasis secara in vivo.…”

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Combination of Cisplatin-Withaferin Based on PEGylated Liposome Nanoparticles as Alternative Therapy for Ovarian Cancer

Yani

Anjani

Narayana

et al. 2020

JMH

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Ovarian cancer is one of the major health problems in gynecology worldwide. Globocan 2012 data shows that ovarian cancer occurs in 239.000 cases, and is placed fourth as the most malignancy occurred in Indonesia. So far, cisplatin is the most effective therapeutic agent, but the high dosage of administration often caused side effects. A new alternative therapy to overcome the problems by using withaferin-A and nanoparticle PEGylated liposome. WFA has the potential effect to reduce cisplatin resistance but has low bioavailability thus, it needs to be encapsulated. This review's goal is to depict the potency of withaferin-A, cisplatin, and PEGylated liposome combination as a therapeutic agent to treat ovarian cancer. The combination of Cisplatin-Withaferin PEGylated Liposome is constructed by the modified thin lipid film hydration method then administered orally. This combination suppresses 70-80% of the ovarian cancer cell growth in vivo and inhibits NGFR from binding to TRKA, prevents cell migration as much as 50%. Nano-Cisferin-Liposome, inhibits migration of ovarian cancer cell significantly through β-catenin signaling through ALDH1 that disturb the spheroid formation, and increase apoptosis event as much 70-80% by increasing ROS production up to 2,5 times. Thus, Nano-Cisferin-Liposome (NCL) has potential as a therapeutic agent for treating ovarian cancer. AbstrakKanker ovarium merupakan masalah kesehatan ginekologi wanita di dunia. Data Global Burden Cancer (Globocan) tahun 2012 menunjukkan kanker ovarium terjadi sebanyak 239.000 kasus, dan menempati urutan ke-empat di Indonesia. Hingga kini, Cisplatin merupakan agen terapi andalan untuk kanker ovarium namun sering menimbulkan efek samping dalam dosis tinggi. Terapi alternatif dapat menjadi solusi untuk mengatasi masalah tersebut dengan memanfaatkan withaferin A (WFA) serta nanopartikel PEGylated liposome. WFA sangat potensial untuk mengurangi resistensi Cisplatin, tetapi memiliki bioavailabilitas rendah sehingga perlu dienkapsulasi. Tujuan tinjauan ini yaitu untuk menggambarkan potensi kombinasi withaferin A, cisplatin, dan PEGylated liposome sebagai pengobatan untuk kanker ovarium. Tinjauan pustaka ini dilakukan dengan menggunakan kata: "kanker ovarium, Withaferin A, Cisplatin dan PEGylated liposome" sebagai kata kunci pada mesin pencarian. Kombinasi Cisplastin-Withaferin dan nanopartikel PEGylated Liposom dilakukan dengan metode thin lipid film hydration yang termodifikasi kemudian diberikan melalui jalur oral. Kombinasi Cisplastin-Withaferin ini dapat menekan pertumbuhan kanker ovarium sebesar 70-80% secara in vivo, menghambat NGFR berikatan dengan TRKA sehingga mencegah terjadinya migrasi sel sebesar 50%, menghambat migrasi sel kanker secara signifikan melalui jalur persinyalan β-catenin oleh ALDH1, meningkatkan apoptosis sebesar 70-80% melalui peningkatan produksi ROS hingga 2,5 kali lipat, serta mampu mengeliminasi CSC. Karena itu, kombinasi ini merupakan salah satu terapi potensial dalam penatalaksanaan kanker ovarium. Kata kunci: Cisplatin; kanker ova...

show abstract

Withaferin A (WFA) inhibits tumor growth and metastasis by targeting ovarian cancer stem cells

Cited by 39 publications

References 63 publications

Vimentin is Required for Tumor Progression and Metastasis in a Mouse Model of Non-Small Cell Lung Cancer

Vimentin is Required for Tumor Progression and Metastasis in a Mouse Model of Non-Small Cell Lung Cancer

Withaferin A: a potential therapeutic agent against COVID-19 infection

Combination of Cisplatin-Withaferin Based on PEGylated Liposome Nanoparticles as Alternative Therapy for Ovarian Cancer

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