Interferon-β sensitizes human malignant melanoma cells to temozolomide-induced apoptosis and autophagy

Abstract

Malignant melanoma is a highly aggressive skin cancer that is highly resistant to chemotherapy. Adjuvant therapy is administered to patients with melanoma that possess no microscopic metastases or have a high risk of developing microscopic metastases. Methylating agents, including dacarbazine (DTIC) and temozolomide (TMZ), pegylated interferon (IFN)-α2b and interleukin-2 have been approved for adjuvant immuno-chemotherapy; however, unsatisfactory results have been reported following the administration of methylating agents. IFN-β has been considered to be a signaling molecule with an important therapeutic potential in cancer. The aim of the present study was to elucidate whether antitumor effects could be augmented by the combination of TMZ and IFN-β in malignant melanoma. We evaluated the efficacy of TMZ and IFN-β by comparing O 6-methylguanine-DNA transferase (MGMT)-proficient and-deficient cells, as MGMT has been reported to be associated with the resistance to methylating agents. Cell viability was determined by counting living cells with a Coulter counter, and apoptosis was analyzed by dual staining with Annexin V Alexa Fluor ® 488 and propidium iodide. The expression of proteins involved in the cell cycle, apoptosis and autophagy was evaluated by western blot analysis. The combined treatment with TMZ and IFN-β suppressed cell proliferation and induced cell cycle arrest. We also demonstrated that a combination of TMZ and IFN-β enhanced apoptosis and autophagy more efficiently compared with TMZ treatment alone. These findings suggest that antitumor activity may be potentiated by IFN-β in combination with TMZ.

Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma

“…TMZ has been known to induce apoptosis in human melanoma cell lines [ 23 , 24 ], which occurs 72–96 h after TMZ treatment [ 23 , 25 ]. To investigate whether decreased cell viability of MGMT-low 1205Lu and HS294T cells is related to TMZ-mediated apoptotic event, we evaluated caspase-3 cleavage 48 h after TMZ treatment.…”

“…These data suggest that TMZ-sensitive and -resistant melanoma cells exhibit distinct characteristics of inflammation and hence respond differently to TMZ treatment. TMZ has been known to induce apoptosis in human melanoma cell lines [23,24], which occurs 72-96 h after TMZ treatment [23,25]. To investigate whether decreased cell viability of MGMT-low 1205Lu and HS294T cells is related to TMZ-mediated apoptotic event, we evaluated caspase-3 cleavage 48 h after TMZ treatment.…”

The Paired Siglecs in Brain Tumours Therapy: The Immunomodulatory Effect of Dexamethasone and Temozolomide in Human Glioma In Vitro Model

“…The lower and upper transwell sections were separated by a 0.4 μM microporous membrane to prevent close contact between glioma and immune cells. Both monocultured and co-cultured cells were exposed to TMZ (Merck, Darmstadt, Germany) and/or Dex (Dexaven, PharmaSwiss, Prague, Czech Republic) for 24 h. Before the treatment, TMZ was freshly dissolved in sterile dimethyl sulfoxide (DMSO, Merck) at a concentration of 0.053 M. The stock solution was added to the culture medium to obtain final concentrations of 10 and 50 μM known to cause the hypermethylating effect whereas the Dex concentration of 10 μM was defined as high clinical level [93][94][95][96].…”

Identification of an IFN-β-associated gene signature for the prediction of overall survival among glioblastoma patients

“…β-interferon (IFN-β) can act as a drug sensitizer, enhancing toxicity against various neoplasias, and is widely used in combination with other antitumor agents, such as nitrosoureas (11)(12)(13). IFN-β sensitizes glioma cells that harbor the unmethylated MGMT promoter and are resistant to temozolomide (11,14,15). Likewise, IFN-β induces loss of spherogenicity and overcomes therapy resistance of glioblastoma stem cells (16).…”