Hyperthermia induces therapeutic effectiveness and potentiates adjuvant therapy with non-targeted and targeted drugs in an in vitro model of human malignant melanoma
In the present study, we have aimed to characterize the intrinsic, extrinsic and ER-mediated apoptotic induction by hyperthermia in an in vitro model of human malignant melanoma and furthermore, to evaluate its therapeutic effectiveness in an adjuvant therapeutic setting characterized by combination...
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| Published in: | Scientific reports Vol. 8; no. 1; pp. 10724 - 16 |
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| Main Authors: | , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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| Abstract | In the present study, we have aimed to characterize the intrinsic, extrinsic and ER-mediated apoptotic induction by hyperthermia in an
in vitro
model of human malignant melanoma and furthermore, to evaluate its therapeutic effectiveness in an adjuvant therapeutic setting characterized by combinational treatments with non-targeted (Dacarbazine & Temozolomide) and targeted (Dabrafenib & Vemurafenib) drugs. Overall, our data showed that both low (43 °C) and high (45 °C) hyperthermic exposures were capable of inducing cell death by activating all apoptotic pathways but in a rather distinct manner. More specifically, low hyperthermia induced extrinsic and intrinsic apoptotic pathways both of which activated caspase 6 only as opposed to high hyperthermia which was mediated by the combined effects of caspases 3, 7 and 6. Furthermore, significant involvement of the ER was evident (under both hyperthermic conditions) suggesting its role in regulating apoptosis via activation of CHOP. Our data revealed that while low hyperthermia activated IRE-1 and ATF6 only, high hyperthermia induced activation of PERK as well suggesting that ultimately these ER stress sensors can lead to the induction of CHOP via different pathways of transmitted signals. Finally, combinational treatment protocols revealed an effect of hyperthermia in potentiating the therapeutic effectiveness of non-targeted as well as targeted drugs utilized in the clinical setting. Overall, our findings support evidence into hyperthermia’s therapeutic potential in treating human malignant melanoma by elucidating the underlying mechanisms of its complex apoptotic induction. |
|---|---|
| AbstractList | In the present study, we have aimed to characterize the intrinsic, extrinsic and ER-mediated apoptotic induction by hyperthermia in an
in vitro
model of human malignant melanoma and furthermore, to evaluate its therapeutic effectiveness in an adjuvant therapeutic setting characterized by combinational treatments with non-targeted (Dacarbazine & Temozolomide) and targeted (Dabrafenib & Vemurafenib) drugs. Overall, our data showed that both low (43 °C) and high (45 °C) hyperthermic exposures were capable of inducing cell death by activating all apoptotic pathways but in a rather distinct manner. More specifically, low hyperthermia induced extrinsic and intrinsic apoptotic pathways both of which activated caspase 6 only as opposed to high hyperthermia which was mediated by the combined effects of caspases 3, 7 and 6. Furthermore, significant involvement of the ER was evident (under both hyperthermic conditions) suggesting its role in regulating apoptosis via activation of CHOP. Our data revealed that while low hyperthermia activated IRE-1 and ATF6 only, high hyperthermia induced activation of PERK as well suggesting that ultimately these ER stress sensors can lead to the induction of CHOP via different pathways of transmitted signals. Finally, combinational treatment protocols revealed an effect of hyperthermia in potentiating the therapeutic effectiveness of non-targeted as well as targeted drugs utilized in the clinical setting. Overall, our findings support evidence into hyperthermia’s therapeutic potential in treating human malignant melanoma by elucidating the underlying mechanisms of its complex apoptotic induction. In the present study, we have aimed to characterize the intrinsic, extrinsic and ER-mediated apoptotic induction by hyperthermia in an in vitro model of human malignant melanoma and furthermore, to evaluate its therapeutic effectiveness in an adjuvant therapeutic setting characterized by combinational treatments with non-targeted (Dacarbazine & Temozolomide) and targeted (Dabrafenib & Vemurafenib) drugs. Overall, our data showed that both low (43 °C) and high (45 °C) hyperthermic exposures were capable of inducing cell death by activating all apoptotic pathways but in a rather distinct manner. More specifically, low hyperthermia induced extrinsic and intrinsic apoptotic pathways both of which activated caspase 6 only as opposed to high hyperthermia which was mediated by the combined effects of caspases 3, 7 and 6. Furthermore, significant involvement of the ER was evident (under both hyperthermic conditions) suggesting its role in regulating apoptosis via activation of CHOP. Our data revealed that while low hyperthermia activated IRE-1 and ATF6 only, high hyperthermia induced activation of PERK as well suggesting that ultimately these ER stress sensors can lead to the induction of CHOP via different pathways of transmitted signals. Finally, combinational treatment protocols revealed an effect of hyperthermia in potentiating the therapeutic effectiveness of non-targeted as well as targeted drugs utilized in the clinical setting. Overall, our findings support evidence into hyperthermia's therapeutic potential in treating human malignant melanoma by elucidating the underlying mechanisms of its complex apoptotic induction. Abstract In the present study, we have aimed to characterize the intrinsic, extrinsic and ER-mediated apoptotic induction by hyperthermia in an in vitro model of human malignant melanoma and furthermore, to evaluate its therapeutic effectiveness in an adjuvant therapeutic setting characterized by combinational treatments with non-targeted (Dacarbazine & Temozolomide) and targeted (Dabrafenib & Vemurafenib) drugs. Overall, our data showed that both low (43 °C) and high (45 °C) hyperthermic exposures were capable of inducing cell death by activating all apoptotic pathways but in a rather distinct manner. More specifically, low hyperthermia induced extrinsic and intrinsic apoptotic pathways both of which activated caspase 6 only as opposed to high hyperthermia which was mediated by the combined effects of caspases 3, 7 and 6. Furthermore, significant involvement of the ER was evident (under both hyperthermic conditions) suggesting its role in regulating apoptosis via activation of CHOP. Our data revealed that while low hyperthermia activated IRE-1 and ATF6 only, high hyperthermia induced activation of PERK as well suggesting that ultimately these ER stress sensors can lead to the induction of CHOP via different pathways of transmitted signals. Finally, combinational treatment protocols revealed an effect of hyperthermia in potentiating the therapeutic effectiveness of non-targeted as well as targeted drugs utilized in the clinical setting. Overall, our findings support evidence into hyperthermia’s therapeutic potential in treating human malignant melanoma by elucidating the underlying mechanisms of its complex apoptotic induction. |
| ArticleNumber | 10724 |
| Author | Mantso, T. Anestopoulos, I. Pappa, A. Panayiotidis, M. I. Simopoulos, C. Chlichlia, K. Botaitis, S. Lampri, E. Voulgaridou, G. P. Franco, R. Kontomanolis, E. N. Vasileiadis, S. Goussetis, G. |
| Author_xml | – sequence: 1 givenname: T. surname: Mantso fullname: Mantso, T. organization: School of Life Sciences, Heriot Watt University, Department of Applied Sciences, Northumbria University – sequence: 2 givenname: S. surname: Vasileiadis fullname: Vasileiadis, S. organization: Department of Obstetrics & Gynecology, Democritus University of Thrace, Department of Molecular Biology & Genetics, Democritus University of Thrace – sequence: 3 givenname: I. surname: Anestopoulos fullname: Anestopoulos, I. organization: Department of Molecular Biology & Genetics, Democritus University of Thrace – sequence: 4 givenname: G. P. surname: Voulgaridou fullname: Voulgaridou, G. P. organization: Department of Molecular Biology & Genetics, Democritus University of Thrace – sequence: 5 givenname: E. surname: Lampri fullname: Lampri, E. organization: Department of Pathology, University of Ioannina – sequence: 6 givenname: S. surname: Botaitis fullname: Botaitis, S. organization: Second Department of Surgery, Democritus University of Thrace – sequence: 7 givenname: E. N. surname: Kontomanolis fullname: Kontomanolis, E. N. organization: Department of Obstetrics & Gynecology, Democritus University of Thrace – sequence: 8 givenname: C. surname: Simopoulos fullname: Simopoulos, C. organization: Second Department of Surgery, Democritus University of Thrace – sequence: 9 givenname: G. surname: Goussetis fullname: Goussetis, G. organization: School of Engineering & Physical Sciences, Heriot Watt University – sequence: 10 givenname: R. surname: Franco fullname: Franco, R. organization: Redox Biology Centre, University of Nebraska, School of Veterinary Medicine & Biomedical Sciences, University of Nebraska – sequence: 11 givenname: K. orcidid: 0000-0003-4952-0675 surname: Chlichlia fullname: Chlichlia, K. organization: Department of Molecular Biology & Genetics, Democritus University of Thrace – sequence: 12 givenname: A. surname: Pappa fullname: Pappa, A. organization: Department of Molecular Biology & Genetics, Democritus University of Thrace – sequence: 13 givenname: M. I. surname: Panayiotidis fullname: Panayiotidis, M. I. email: m.panagiotidis@northumbria.ac.uk organization: School of Life Sciences, Heriot Watt University, Department of Applied Sciences, Northumbria University |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30013176$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
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| Snippet | In the present study, we have aimed to characterize the intrinsic, extrinsic and ER-mediated apoptotic induction by hyperthermia in an
in vitro
model of human... In the present study, we have aimed to characterize the intrinsic, extrinsic and ER-mediated apoptotic induction by hyperthermia in an in vitro model of human... Abstract In the present study, we have aimed to characterize the intrinsic, extrinsic and ER-mediated apoptotic induction by hyperthermia in an in vitro model... |
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| Title | Hyperthermia induces therapeutic effectiveness and potentiates adjuvant therapy with non-targeted and targeted drugs in an in vitro model of human malignant melanoma |
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