The curcumin analog DM-1 induces apoptotic cell death in melanoma

Faião-Flores, Fernanda; Suárez, José Agustín Quincoces; Maria‐Engler, Silvya Stuchi; Soto‐Cerrato, Vanessa; Pérez-Tomás, Ricardo; Maria, Durvanei Augusto

doi:10.1007/s13277-013-0653-y

Cited by 21 publications

(23 citation statements)

References 37 publications

(36 reference statements)

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“…Additionally, apoptosis was also confirmed by apoptotic bodies in human melanoma cell line. DM-1 antitumor therapy in vivo showed tumor burden decrease with DM-1 monotherapy or in combination with Dacarbazine, besides survival rate increase [13].…”

Section: Discussionmentioning

confidence: 95%

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Bcl-2 family proteins and cytoskeleton changes involved in DM-1 cytotoxic effect on melanoma cells

et al. 2013

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Melanoma is one of the most aggressive types of skin cancer and its incidence rate is still increasing. All existing treatments are minimally effective. Consequently, new therapeutic agents for melanoma treatment should be developed. The DM-1 compound is a curcumin analog that possesses several curcumin characteristics, such as antiproliferative, antitumor and antimetastatic properties. The aim of this study was to evaluate the different signaling pathways involved in the cytotoxic effect of DM-1 on melanoma cells.The apoptotic process and cytoskeletal changes were evaluated by immunoblotting and immunofluorescence, respectively, in melanoma cells.After DM-1 treatment, SK-MEL-5 melanoma cells showed actin filaments disorganization with spicules formation throughout the cytoskeleton and significant reduction of focal adhesion as well as they were present only at cell extremities, conferring a poor connection between the cell and the substrate. Besides this, there was significant filopodium retraction and loss of typical cytoskeleton scaffold. These modifications contributed to cell detachment followed by cell death.Furthermore, DM-1-induced apoptosis was triggered by multiple Bcl-2 proteins involved in both the extrinsic and the intrinsic apoptotic pathways. SK-MEL-5 cells showed a death mechanism mainly by Bcl-2/Bax ratio decrease, whereas A375 cells presented apoptosis induction by Mcl-1 and Bcl-xL downregulation. In SK-MEL-5 and A375 melanoma cells, there were a significant increase in the active form of caspase 9 and the inactive form of the effector caspase 3 was decreased in both cell lines. Expression of cleaved Parp was increased after DM-1 treatment in these melanoma cell lines, demonstrating 2 that the apoptotic process occurred. Altogether, these data elucidate the cellular and molecular mechanisms involved in the cytotoxicity induced by the antitumor agent DM-1 in melanoma cells.

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Section: Discussionmentioning

confidence: 95%

“…Activated pro-apoptotic proteins like Bid and Bax cause the release of the apoptogenic cytochrome-c from the mitochondrial membrane, leading to caspase cascade activation [44]. DM-1 also induces cytochrome-c release and electric mitochondrial membrane potential decrease in B16F10 melanoma cells after 6 h of treatment [13].…”

Section: Discussionmentioning

confidence: 99%

Bcl-2 family proteins and cytoskeleton changes involved in DM-1 cytotoxic effect on melanoma cells

et al. 2013

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“…One strategy for circumventing this problem could be the creation of synthetic analogs. There were several reports on the new synthetic analogs or derivatives of curcumin to enhance the anti-proliferation activity (Faião-Flores et al, 2013;Kumaravel et al, 2012;Xiao et al, 2012), but these analogs generally led to cancer cell death via the apoptosis pathway.…”

Section: Introductionmentioning

confidence: 99%

A synthetic curcumin derivative hydrazinobenzoylcurcumin induces autophagy in A549 lung cancer cells

Zhou

Zhang

et al. 2013

Pharmaceutical Biology

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Context: Curcumin exhibits growth-suppressive activity against a variety of cancer cells, but low bioavailability restricts its application in chemotherapeutic trials. Nowadays, a growing number of curcumin derivatives or analogs are known, hoping to replace curcumin and circumvent this problem. Hydrazinobenzoylcurcumin (HBC) has been synthesized and identified as a potent inhibitor of cell proliferation in previous reports. Objective: This study presents a novel mechanism of cell autophagy induced by HBC in the human non-small lung epithelial carcinoma (A549) cells. Materials and methods: Cells were cultured and treated with HBC at different concentrations (10-80 mM) and at different time periods (1-24 h). Microscopic analysis was used to detect the morphology changes and autophagolysosomes of A549 cells. An acridine orange staining assay was conducted to evaluate the autophagolysosomes and autophagic vacuoles was analyzed by monodansylcadaverine (MDC) and GFP-LC3 transfection analysis. Western blotting was used to assess the conversion of microtubule-associated protein light chain 3 (LC3). Results: HBC could induce A549 cells autophagolysosomes formation in a dose and timedependent manner and the inhibitory rate of HBC (80 mM) on the viability of A549 cells reached 76.68 AE 5.81% after 24 h of treatment. Autophagic vacuoles increased in a concentrationdependent manner in HBC-treated cell. Furthermore, conversion of LC3-I to LC3-II, accumulation of GFP-tagged LC3 positive intracellular vacuoles and increased fusion of autophagosomes with lysosomes suggested the occurrence of autophagy. Conclusion: Our data indicate that HBC induced A549 cell autophagy, which is a novel cell death mechanism induced by curcumin derivatives.

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“…It was found that DM‐1 alone and in combination with DTIC induces apoptosis via the cleavage of caspase‐8, −3 and −9. These results indicated that DM‐1 shows therapeutic effects on melanoma via a preferential intrinsic apoptotic pathway by decreasing Bcl‐2/Bax ratio …”

Section: Curcumin Analogs As Powerful Tools In Melanoma Therapymentioning

confidence: 82%

“…Moreover, Faião‐Flores et al . revealed that curcumin analogue DM‐1, alone or in combination with dacarbazine (DTIC), shows anti‐tumor effects as it inhibited melanoma progression in a melanoma mouse model . In addition, no toxicological changes were observed in organs such as the spleen, kidneys, liver and lungs after the administration of DM‐1, either alone or in combination with DTIC.…”

Section: Curcumin Analogs As Powerful Tools In Melanoma Therapymentioning

confidence: 99%

Curcumin: A new candidate for melanoma therapy?

Mirzaei

Naseri

Rezaee

et al. 2016

Intl Journal of Cancer

229

195

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Melanoma remains among the most lethal cancers and, in spite of great attempts that have been made to increase the life span of patients with metastatic disease, durable and complete remissions are rare. Plants and plant extracts have long been used to treat a variety of human conditions; however, in many cases, effective doses of herbal remedies are associated with serious adverse effects. Curcumin is a natural polyphenol that shows a variety of pharmacological activities including anti-cancer effects, and only minimal adverse effects have been reported for this phytochemical. The anti-cancer effects of curcumin are the result of its anti-angiogenic, pro-apoptotic and immunomodulatory properties. At the molecular and cellular level, curcumin can blunt epithelial-to-mesenchymal transition and affect many targets that are involved in melanoma initiation and progression (e.g., BCl2, MAPKS, p21 and some microRNAs). However, curcumin has a low oral bioavailability that may limit its maximal benefits. The emergence of tailored formulations of curcumin and new delivery systems such as nanoparticles, liposomes, micelles and phospholipid complexes has led to the enhancement of curcumin bioavailability. Although in vitro and in vivo studies have demonstrated that curcumin and its analogues can be used as novel therapeutic agents in melanoma, curcumin has not yet been tested against melanoma in clinical practice. In this review, we summarized reported anti-melanoma effects of curcumin as well as studies on new curcumin formulations and delivery systems that show increased bioavailability. Such tailored delivery systems could pave the way for enhancement of the anti-melanoma effects of curcumin.

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The curcumin analog DM-1 induces apoptotic cell death in melanoma

Cited by 21 publications

References 37 publications

Bcl-2 family proteins and cytoskeleton changes involved in DM-1 cytotoxic effect on melanoma cells

Bcl-2 family proteins and cytoskeleton changes involved in DM-1 cytotoxic effect on melanoma cells

A synthetic curcumin derivative hydrazinobenzoylcurcumin induces autophagy in A549 lung cancer cells

Curcumin: A new candidate for melanoma therapy?

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