Novel synthetic analogs of diallyl disulfide triggers cell cycle arrest and apoptosis via ROS generation in MIA PaCa-2 cells

Saini, Vikas; Manral, Apra; Arora, R; Meena, Poonam; Gusain, Siddharth; Saluja, Daman; Tiwari, Manisha

doi:10.1016/j.pharep.2017.03.006

Cited by 22 publications

(14 citation statements)

References 22 publications

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“…It is well know that excessive ROS production is associated with the induction of cell death and differentiation, fascinated in therapeutic strategy [ 37 ]. Numerous small molecules used to treat various malignant tumors have been shown to stimulate high level of ROS [ 33 , 38 ]. Our results also concurrent with them, shown ROS mediated cytotoxicity and loss of cancer cell integrity.…”

Section: Discussionmentioning

confidence: 99%

Novel allylated monocarbonyl analogs of curcumin induce mitotic arrest and apoptosis by reactive oxygen species-mediated endoplasmic reticulum stress and inhibition of STAT3

et al. 2017

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Curcumin is a promising active compound from a natural source and is extensively being tested in clinical trials because of its bio-functional properties. However, poor bioavailability has hampered its clinical application. Numerous attempts have been made in our laboratory to discover analogs of curcumin with enhanced bioavailability and superior pharmacological activity. In this study, we have investigated a new series of allylated monocarbonyl analogs of curcumin (MAC) and tested their effect on gastric cancer cells. Our results show six MAC that selectively targeted cancer cell lines to inhibit growth and induce apoptosis. This activity was achieved by generation of reactive oxygen species (ROS) by MAC. We selected one effective MAC (CA10) for further investigation and show that CA10 inhibits cell growth by causing G2/M cell cycle arrest and induction of apoptotic death. CA10 induced ROS generation and subsequent activation of endoplasmic reticulum (ER) stress and inhibition of signal transducer and activator of transcription 3 (STAT3) phosphorylation, inhibits cancer cell proliferation. These anti-tumor activities of CA10 were confirmed in gastric cancer xenografts. CA10 induced ROS, activated the ER stress pathway and inhibited STAT3 phosphorylation and gastric xenografts tumor growth in mice. Our studies provide experimental evidence that MAC CA10 effectively targets gastric cancer in preclinical models by enhancing ROS and ROS-mediated signaling.

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Section: Discussionmentioning

confidence: 99%

Novel allylated monocarbonyl analogs of curcumin induce mitotic arrest and apoptosis by reactive oxygen species-mediated endoplasmic reticulum stress and inhibition of STAT3

et al. 2017

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“…Several studies have shown that DADS (<1.25 mg/L) generates ROS and that this effect is important for the induction of differentiation . DADS can induce ROS production, which is often associated with cancer progression . Indeed, we found that intracellular levels of ROS were increased after treatment of HL‐60 cells with DADS.…”

Section: Discussionmentioning

confidence: 58%

Diallyl disulfide down‐regulates calreticulin and promotes C/EBPα expression in differentiation of human leukaemia cells

Sun

et al. 2018

J Cellular Molecular Medi

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Diallyl disulfide (DADS), the main active component of the cancer fighting allyl sulfides found in garlic, has shown potential as a therapeutic agent in various cancers. Previous studies showed DADS induction of HL‐60 cell differentiation involves down‐regulation of calreticulin (CRT). Here, we investigated the mechanism of DADS‐induced differentiation of human leukaemia cells and the potential involvement of CRT and CCAAT enhancer binding protein‐α (C/EBPα). We explored the expression of CRT and C/EBPα in clinical samples (20 healthy people and 19 acute myeloid leukaemia patients) and found that CRT and C/EBPα expressions were inversely correlated. DADS induction of differentiation of HL‐60 cells resulted in down‐regulated CRT expression and elevated C/EBPα expression. In severe combined immunodeficiency mice injected with HL‐60 cells, DADS inhibited the growth of tumour tissue and decreased CRT levels and increased C/EBPα in vivo. We also found that DADS‐mediated down‐regulation of CRT and up‐regulation of C/EBPα involved enhancement of reactive oxidative species. RNA immunoprecipitation revealed that CRT bound C/EBPα mRNA, indicating its regulation of C/EBPα mRNA degradation by binding the UG‐rich element in the 3′ untranslated region of C/EBPα. In conclusion, the present study demonstrates the C/EBPα expression was correlated with CRT expression in vitro and in vivo and the molecular mechanism of DADS‐induced leukaemic cell differentiation.

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“…Besides, treatment with DADS also induces G2/M arrests in pancreatic [120], ovarian [121], and colon cancer cells [122] by promoting DNA-damage and activating mitochondria apoptotic pathways. In summary, H2S donors regulate cell cycle progression by interacting with cell cycle regulators and checkpoints, suggesting the potential of these compounds in cancer treatment.…”

Section: H 2 S Donor Blocks Cell Cyclementioning

confidence: 99%

“…It has also been shown that the administration of ADT-OH can enhance anti-cancer activities in melanoma by reducing makorin ring finger protein 1 levels and preventing the degradation of IkBα, resulting in the accumulation of apoptotic adaptor protein Fas-associated protein with death domain and inhibition of NF-кB, respectively [155]. In different cancer types, treatment with DATS has been shown to induce cell death by promoting mitochondria-mediated DNA damage [114] and by regulating AMPK [117], c-JUN N-terminal kinases (JNK) [119], PI3K/AKT [120], p38MAPK [156], and NF-кB [157] signaling pathways. Likewise, DADS treatment suppresses cancer progression by facilitating DNA damage [120] and inhibiting PI3K/AKT/mTOR [142,143] and NF-кB pathways [32].…”

Section: H 2 S Donor Induces Apoptosismentioning

confidence: 99%

Role of hydrogen sulfide donors in cancer development and progression

et al. 2021

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In recent years, a vast number of potential cancer therapeutic targets have emerged. However, developing efficient and effective drugs for the targets is of major concern. Hydrogen sulfide (H2S), one of the three known gasotransmitters, is involved in the regulation of various cellular activities such as autophagy, apoptosis, migration, and proliferation. Low production of H2S has been identified in numerous cancer types. Treating cancer cells with H2S donors is the common experimental technique used to improve H2S levels; however, the outcome depends on the concentration/dose, time, cell type, and sometimes the drug used. Both natural and synthesized donors are available for this purpose, although their effects vary independently ranging from strong cancer suppressors to promoters. Nonetheless, numerous signaling pathways have been reported to be altered following the treatments with H2S donors which suggest their potential in cancer treatment. This review will analyze the potential of H2S donors in cancer therapy by summarizing key cellular processes and mechanisms involved.

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Novel synthetic analogs of diallyl disulfide triggers cell cycle arrest and apoptosis via ROS generation in MIA PaCa-2 cells

Abstract: Taken together, the anti-proliferative effects of compound 5b were attributed to intracellular ROS accumulation, which in turn, triggers apoptosis by mediating DNA damage-induced G2/M phase arrest and evoking mitochondrial apoptotic pathway in MIA PaCa-2 cells.

Cited by 22 publications

References 22 publications

Novel allylated monocarbonyl analogs of curcumin induce mitotic arrest and apoptosis by reactive oxygen species-mediated endoplasmic reticulum stress and inhibition of STAT3

Novel allylated monocarbonyl analogs of curcumin induce mitotic arrest and apoptosis by reactive oxygen species-mediated endoplasmic reticulum stress and inhibition of STAT3

Diallyl disulfide down‐regulates calreticulin and promotes C/EBPα expression in differentiation of human leukaemia cells

Role of hydrogen sulfide donors in cancer development and progression

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