Unraveling the molecular mechanisms and the potential chemopreventive/therapeutic properties of natural compounds in melanoma

Fontana, Fabrizio; Raimondi, Mario; Domizio, Alessandro Di; Moretti, Roberta M.; Limonta, Patrizia

doi:10.1016/j.semcancer.2019.06.011

Cited by 29 publications

(16 citation statements)

References 378 publications

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“…Currently, many studies are focused on the paraptosis induced by natural products in cancer cells [11]. δ-TT, a vitamin E derivative endowed with powerful anti-tumor properties [18][19][20][21][22], has been shown to trigger this type of alternative cell death in colon and prostate cancer [24][25][26]. Herein, we investigated whether this compound could activate the paraptotic cascade in melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

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Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

et al. 2021

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Melanoma is an aggressive tumor with still poor therapy outcomes. δ-tocotrienol (δ-TT) is a vitamin E derivative displaying potent anti-cancer properties. Previously, we demonstrated that δ-TT triggers apoptosis in human melanoma cells. Here, we investigated whether it might also activate paraptosis, a non-canonical programmed cell death. In accordance with the main paraptotic features, δ-TT was shown to promote cytoplasmic vacuolization, associated with endoplasmic reticulum/mitochondrial dilation and protein synthesis, as well as MAPK activation in A375 and BLM cell lines. Moreover, treated cells exhibited a significant reduced expression of OXPHOS complex I and a marked decrease in oxygen consumption and mitochondrial membrane potential, culminating in decreased ATP synthesis and AMPK phosphorylation. This mitochondrial dysfunction resulted in ROS overproduction, found to be responsible for paraptosis induction. Additionally, δ-TT caused Ca2+ homeostasis disruption, with endoplasmic reticulum-derived ions accumulating in mitochondria and activating the paraptotic signaling. Interestingly, by using both IP3R and VDAC inhibitors, a close cause-effect relationship between mitochondrial Ca2+ overload and ROS generation was evidenced. Collectively, these results provide novel insights into δ-TT anti-melanoma activity, highlighting its ability to induce mitochondrial dysfunction-mediated paraptosis. Graphic Abstract δ-tocotrienol induces paraptotic cell death in human melanoma cells, causing endoplasmic reticulum dilation and mitochondrial swelling. These alterations induce an impairment of mitochondrial function, ROS production and calcium overload.

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Section: Discussionmentioning

confidence: 99%

“…Tocotrienols (TTs) are vitamin E derivatives displaying potent anti-tumor properties [18][19][20][21][22]. We previously demonstrated that the δ isomer could induce ER stress-related apoptosis in A375 and BLM human melanoma cells, while sparing normal melanocytes [23].…”

Section: Introductionmentioning

confidence: 99%

Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

et al. 2021

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“…Indeed, several natural compounds have been shown to induce ROS‐related cell death in different types of tumour, including OC. 28 , 29 , 30 , 31 Regarding TTs, the γ isoform has been reported to trigger mitochondrial dysfunction‐ and oxidative imbalance‐associated apoptosis in gastric adenocarcinoma cells, as well as to sensitize colorectal cancer cells to TRAIL proapoptotic activity via ROS overproduction. 32 , 33 Similarly, δ‐TT can cause ROS‐mediated cytotoxicity in various models of breast and prostate cancer, 11 , 34 while α‐tocopheryl succinate, a redox‐silent Vitamin E analogue, has been demonstrated to stimulate cytochrome c release in neuroblastoma through a severe alteration of redox homeostasis.…”

Section: Discussionmentioning

confidence: 99%

δ‐Tocotrienol sensitizes and re‐sensitizes ovarian cancer cells to cisplatin via induction of G1 phase cell cycle arrest and ROS/MAPK‐mediated apoptosis

et al. 2021

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Ovarian cancer (OC) is the seventh most commonly diagnosed cancer among women worldwide, representing the deadliest form of gynaecologic malignancy. 1 Due to the lack of early symptoms and consequent difficulties in detection, most OC patients are diagnosed at advanced stages. 2,3 Current standard treatment for patients with advanced OC includes primary tumour cytoreductive surgery followed by chemotherapy. 4 Platinum is commonly used in OC chemotherapy. 4 The efficacy of this DNA-damaging agent seems to be correlated with its ability to inhibit the proliferation and induce apoptosis of cancer cells. However, despite being initially responsive, about 70% of patients

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“…The incidence of malignant melanoma continues to rise worldwide, but the success rate of current treatment strategies for metastatic melanoma is relatively low, and most emerging anti-melanoma therapies have serious adverse reactions, which all highlight the necessity of developing safe and effective new targeted drugs for melanoma. 21 , 22 Natural products and their derivatives have shown great potential in the prevention and treatment of human cancer, 23 , 24 such as Vitexin, 25 Morin, 26 and Weimaining Capsules, a second-class anti-tumor drug successfully developed with tannin compounds as effective ingredients. 27 This indicates that certain compounds derived from nature tend to have certain biological activities and are promising as new drugs for the treatment of diseases.…”

Section: Discussionmentioning

confidence: 99%

Acetone Extract of Cornus officinalis Leaves Exerts Anti-Melanoma Effects via Inhibiting STAT3 Signaling

Zeng

Wang

et al. 2021

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Purpose This research aims to investigate the intervention and mechanism of 50% acetone extract of C. officinalis leaves (SZYY) on melanoma xenografts. Patients and Methods Tumor size and cardiac function were measured via ultrasound. The accumulation of 2-deoxy-D-glucose (2-DG) in tumor tissue was examined with near-infrared in vivo imaging. Flow cytometry was performed to assess apoptosis and reactive oxygen species (ROS) levels in tumor and immune cells in spleen. The levels of inflammatory cytokines in serum were detected by cytometric bead array. The expression of proliferation-, apoptosis-, and angiogenesis-related proteins in tumor cells was measured to evaluate the underlying mechanisms. Subsequently, the effects of four compounds separated from SZYY on the proliferation and migration of A375 cells and STAT3 signaling were examined. The peak identification and contents of the four components were performed via high-performance liquid chromatography (HPLC). Finally, we evaluated the inhibitory effects of STAT3 overexpression on the cytotoxic activity of four constituents in A375 cells. Results SZYY inhibited the growth and glycolysis of melanoma xenograft in mice, improved cardiac function, increased the percentages of macrophages, neutrophils, and lymphocytes in spleen, reduced the levels of IL-6, IL-17A, TNF-α, and IFN-γ in serum, promoted apoptosis and oxidative stress in tumor tissues, and inhibited STAT3 phosphorylation and expression of angiogenic factors. Chemical analysis showed that SZYY is rich in loganin, rutin, triohimas C, and triohimas D, which all could restrain the proliferation and migration of A375 cells and inhibit the phosphorylation and nuclear translocation of STAT3. Moreover, STAT3 overexpression could diminish the cytotoxic activity of four compounds on A375 cells. Conclusion SZYY could exert anti-melanoma effects via inhibiting STAT3 signaling to induce apoptosis and inhibit tumor angiogenesis. Its active ingredients might be loganin, rutin, triohimas C, and triohimas D.

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Unraveling the molecular mechanisms and the potential chemopreventive/therapeutic properties of natural compounds in melanoma

Cited by 29 publications

References 378 publications

Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

Ca2+ overload- and ROS-associated mitochondrial dysfunction contributes to δ-tocotrienol-mediated paraptosis in melanoma cells

δ‐Tocotrienol sensitizes and re‐sensitizes ovarian cancer cells to cisplatin via induction of G1 phase cell cycle arrest and ROS/MAPK‐mediated apoptosis

Acetone Extract of Cornus officinalis Leaves Exerts Anti-Melanoma Effects via Inhibiting STAT3 Signaling

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