Synergic Effects of Doxorubicin and Melatonin on Apoptosis and Mitochondrial Oxidative Stress in MCF-7 Breast Cancer Cells: Involvement of TRPV1 Channels
- 819 Downloads
Transient receptor transient receptor potential vanilloid 1 (TRPV1) is a Ca2+-permeable channel gated by oxidative stress and capsaicin (CAP) and modulated by melatonin (MEL) and capsazepine (CPZ). A combination of doxorubicin (DOX) and MEL may offer a potential therapy for breast cancer by exerting antitumor and anti-apoptotic effects and modulating Ca2+ influx and TRPV1 activity. We aimed to investigate the effects of MEL and DOX on the oxidative toxicity of MCF-7 human breast cancer cells, in addition to the activity of the TRPV1 channel and apoptosis. The MCF-7 cells were divided into the following six treatment groups: control, incubated with MEL (0.3 mM), incubated with 0.5 μM DOX, incubated with 1 μM DOX, incubated with MEL + 0.5 μM DOX, or incubated with MEL + 1 μM DOX. The intracellular free Ca2+ concentration was higher in the DOX groups than in the control, and the concentration was decreased by MEL. The intracellular free Ca2+ concentration was further increased by treatment with the TRPV1 channel activator CAP (0.01 mM), and it was decreased by the CPZ (0.1 mM). The intracellular production of reactive oxygen species, mitochondrial membrane depolarization, apoptosis level, procaspase 9 and PARP activities, and caspase 3 and caspase 9 activities were higher in the DOX and MEL groups than in the control. Apoptosis and the activity of caspase 9 were further increased in the DOX plus MEL groups. Taken together, the findings indicate that MEL supported the effects of DOX by activation of TRPV1 and apoptosis, as well as by inducing MCF-7 cell death. As the apoptosis and caspase activity of cancer cells increase because of their elevated metabolism, MEL may be useful in supporting their apoptotic capacity.
KeywordsApoptosis Breast cancer cells Calcium signaling Doxorubicin Mitochondria Oxidative stress
Intracellular free Ca2+ concentration
Ethylene glycol-bis[2-aminoethyl-ether]-N,N,N,N-tetraacetic acid
Poly (ADP-ribose) polymerase
Reactive oxygen species
Transient receptor potential
Transient receptor potential melastatin 2
Transient receptor potential vanilloid 1
MN formulated the present hypothesis and was responsible for writing the report. BÇ, ISÖ, and PAK were responsible for the analysis of the data.
This study received no financial support.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflicts of interest.
- Chen SJ, Hoffman NE, Shanmughapriya S, Bao L, Keefer K, Conrad K, Merali S, Takahashi Y, Abraham T, Hirschler-Laszkiewicz I, Wang J, Zhang XQ, Song J, Barrero C, Shi Y, Kawasawa YI, Bayerl M, Sun T, Barbour M, Wang HG, Madesh M, Cheung JY, Miller BA (2014) A splice variant of the human ion channel TRPM2 modulates neuroblastoma tumor growth through hypoxia-inducible factor (HIF)-1/2α. J Biol Chem 289:36284–36302CrossRefPubMedPubMedCentralGoogle Scholar
- Ip SW, Lan SH, Lu HF, Huang AC, Yang JS, Lin JP, Huang HY, Lien JC, Ho CC, Chiu CF, Wood W, Chung JG (2012) Capsaicin mediates apoptosis in human nasopharyngeal carcinoma NPC-TW 039 cells through mitochondrial depolarization and endoplasmic reticulum stress. Hum Exp Toxicol 31(6):539–549CrossRefPubMedGoogle Scholar
- Nazıroğlu M, Çelik Ö, Özgül C, Çiğ B, Doğan S, Bal R, Gümral N, Rodríguez AB, Pariente JA (2012) Melatonin modulates wireless (2.45 GHz)-induced oxidative injury through TRPM2 and voltage gated Ca(2+) channels in brain and dorsal root ganglion in rat. Physiol Behav 105:683–692CrossRefPubMedGoogle Scholar
- Özdemir ÜS, Nazıroğlu M, Şenol N, Ghazizadeh V (2015) Hypericum perforatum attenuates spinal cord injury-induced oxidative stress and apoptosis in the dorsal root ganglion of rats: involvement of TRPM2 and TRPV1 channels. Mol Neurobiol 23:1–12Google Scholar
- Radogna F, Paternoster L, De Nicola M, Cerella C, Ammendola S, Bedini A, Tarzia G, Aquilano K, Ciriolo M, Ghibelli L (2009) Rapid and transient stimulation of intracellular reactive oxygen species by melatonin in normal and tumor leukocytes. Toxicol Appl Pharmacol 239:37–45CrossRefPubMedGoogle Scholar