N-alkyl triphenylvinylpyridinium conjugated dihydroartemisinin perturbs mitochondrial functions resulting in enhanced cancer versus normal cell toxicity

Varmazyad, Mahboubeh; Modi, Mira M.; Kalen, Amanda L.; Sarsour, Ehab H.; Wagner, Brett A.; Du, Juan; Schultz, Michael; Buettner, Garry R.; Pigge, F. Christopher; Goswami, Prabhat C.

doi:10.1016/j.freeradbiomed.2021.01.050

Cited by 3 publications

(3 citation statements)

References 71 publications

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“…[7][8][9][10][11] The role of DHA in regulating tumorigenesis is being increasingly appreciated as its preferential antiproliferative effects on cancer versus normal cells have been revealed. 12 In this study, we found that DHA not only inhibited CC cell proliferation but also synergistically enhanced the cytotoxicity of oxaliplatin in CC cells. We found that DHA can reduce the expression level of prohibitin 2 (PHB2) in a ubiquitin-dependent manner.…”

Section: According To the Latest Version Of The National Comprehensivementioning

confidence: 53%

“…Increasing evidence has shown that DHA can inhibit the growth of various cancers, including breast cancer, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, CC, and cervical cancer 7–11 . The role of DHA in regulating tumorigenesis is being increasingly appreciated as its preferential antiproliferative effects on cancer versus normal cells have been revealed 12 …”

Section: Introductionmentioning

confidence: 99%

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Dihydroartemisinin synergistically enhances the cytotoxic effects of oxaliplatin in colon cancer by targeting the PHB2‐RCHY1 mediated signaling pathway

Wang

Zheng

Chai

et al. 2022

Molecular Carcinogenesis

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Dihydroartemisinin (DHA) has recently attracted increasing attention for its low toxicity and high antitumor activity. DHA has been reported to have synergistic anticancer effects with a variety of drugs in the clinic; however, the molecular mechanism by which DHA inhibits tumorigenesis and improves oxaliplatin cytotoxicity in colon cancer cells is still not well understood. In this study, we found that DHA can inhibit cell proliferation and colony formation in a dose-dependent manner. Prohibitin 2 (PHB2) is a potential target by which DHA exerts its antitumor and cytotoxic effects.The function and molecular mechanism of PHB2 in colon cancer tumorigenesis were fully studied to determine the regulatory mechanism between DHA and PHB2. We found that PHB2, a mitochondrial inner membrane scaffold protein, has a higher expression level in colon cancer tissues than in adjacent nontumor tissues and is mainly localized in mitochondria. Overexpression of PHB2 can promote cell proliferation and colony formation in vitro and accelerate tumor growth in vivo. We also found that the expression level of PHB2 was inversely related to the cytotoxicity of DHA and oxaliplatin in colon cancer cells. The molecular mechanism of PHB2 in tumorigenesis and cancer therapy was further studied. The results showed that 20 μM DHA can downregulate PHB2 expression in a ubiquitylation-dependent manner and subsequently block PHB2-induced RCHY1 upregulation and p53 and p21 downregulation. In this process, RCHY1 is necessary for PHB2 to play a tumor-promoting role. Thus,

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Section: According To the Latest Version Of The National Comprehensivementioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin synergistically enhances the cytotoxic effects of oxaliplatin in colon cancer by targeting the PHB2‐RCHY1 mediated signaling pathway

Wang

Zheng

Chai

et al. 2022

Molecular Carcinogenesis

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“…Moreover, DHA could not only reduce the tumor growth but also partly alleviated the toxicity of cisplatin in the tumor-xenograft mice model [ 68 ]. In addition, a recent study also reported that DHA-based therapeutics exhibit a preferential antitumor effect on human melanoma and pancreatic cancer cells significantly, rather than normal human fibroblasts [ 69 ]. The level of intracellular free iron can serve as a criterion to determine which type of cancer is more sensitive to ferroptosis [ 70 ].…”

Section: Discussionmentioning

confidence: 99%

Repurposing Dihydroartemisinin to Combat Oral Squamous Cell Carcinoma, Associated with Mitochondrial Dysfunction and Oxidative Stress

Shi

Luo

et al. 2023

Oxidative Medicine and Cellular Longevity

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Oral squamous cell carcinoma (OSCC), with aggressive locoregional invasion, has a high rate of early recurrences and poor prognosis. Dihydroartemisinin (DHA), as a derivative of artemisinin, has been found to exert potent antitumor activity. Recent studies reported that DHA suppresses OSCC cell growth and viability through the regulation of reactive oxygen species (ROS) production and mitochondrial calcium uniporter. However, the mechanism underlying the action of DHA on OSCCs remains elusive. In the study, we observed that 159 genes were remarkably misregulated in primary OSCC tumors associated with DHA-inhibited pathways, supporting that OSCCs are susceptible to DHA treatment. Herein, our study showed that DHA exhibited promising effects to suppress OSCC cell growth and survival, and single-cell colony formation. Interestingly, the combination of DHA and cisplatin (CDDP) significantly reduced the toxicity of CDDP treatment alone on human normal oral cells (NOK). Moreover, DHA remarkably impaired mitochondrial structure and function, and triggered DNA damage and ROS generation, and activation of mitophagy. In addition, DHA induced leakage of cytochrome C and apoptosis-inducing factor (AIF) from mitochondria, elevated Bax/cleaved-caspase 3 expression levels and compromised Bcl2 protein expression. In the OSCC tumor-xenograft mice model, DHA remarkably suppressed tumor growth and induced apoptosis of OSCCs in vivo. Intriguingly, a selective mitophagy inhibitor Mdivi-1 could significantly reinforce the anticancer activity of DHA treatment. DHA and Mdivi-1 can synergistically suppress OSCC cell proliferation and survival. These data uncover a previously unappreciated contribution of the mitochondria-associated pathway to the antitumor activity of DHA on OSCCs. Our study shed light on a new aspect of a DHA-based therapeutic strategy to combat OSCC tumors.

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Dihydroartemisinin‐driven TOM70 inhibition leads to mitochondrial destabilization to induce pyroptosis against lung cancer

Li,

Hu,

Han

et al. 2024

Phytotherapy Research

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Enhancement of malignant cell immunogenicity to relieve immunosuppression of lung cancer microenvironment is essential in lung cancer treatment. In previous study, we have demonstrated that dihydroartemisinin (DHA), a kind of phytopharmaceutical, is effective in inhibiting lung cancer cells and boosting their immunogenicity, while the initial target of DHA's intracellular action is poorly understood. The present in‐depth analysis aims to reveal the influence of DHA on the highly expressed TOM70 in the mitochondrial membrane of lung cancer. The affinity of DHA and TOM70 was analyzed by microscale thermophoresis (MST), pronase stability, and thermal stability. The functions and underlying mechanism were investigated using western blots, qRT‐PCR, flow cytometry, and rescue experiments. TOM70 inhibition resulted in mtDNA damage and translocation to the cytoplasm from mitochondria due to the disruption of mitochondrial homeostasis. Further ex and in vivo findings also showed that the cGAS/STING/NLRP3 signaling pathway was activated by mtDNA and thereby malignant cells underwent pyroptosis, leading to enhanced immunogenicity of lung cancer cells in the presence of DHA. Nevertheless, DHA‐induced mtDNA translocation and cGAS/STING/NLRP3 mobilization were synchronously attenuated when TOM70 was replenished. Finally, DHA was demonstrated to possess potent anti‐lung cancer efficacy in vitro and in vivo. Taken together, these data confirm that TOM70 is an important target for DHA to disturb mitochondria homeostasis, which further activates STING and arouses pyroptosis to strengthen immunogenicity against lung cancer thereupon. The present study provides vital clues for phytomedicine‐mediated anti‐tumor therapy.

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N-alkyl triphenylvinylpyridinium conjugated dihydroartemisinin perturbs mitochondrial functions resulting in enhanced cancer versus normal cell toxicity

Cited by 3 publications

References 71 publications

Dihydroartemisinin synergistically enhances the cytotoxic effects of oxaliplatin in colon cancer by targeting the PHB2‐RCHY1 mediated signaling pathway

Dihydroartemisinin synergistically enhances the cytotoxic effects of oxaliplatin in colon cancer by targeting the PHB2‐RCHY1 mediated signaling pathway

Repurposing Dihydroartemisinin to Combat Oral Squamous Cell Carcinoma, Associated with Mitochondrial Dysfunction and Oxidative Stress

Dihydroartemisinin‐driven TOM70 inhibition leads to mitochondrial destabilization to induce pyroptosis against lung cancer

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