Experimental demonstration of plasticity in the heat shock response of the intertidal mussel Mytilus californianus

Heat shock inductors have potential as treatment for degenerative and protein misfolding diseases. Dimethyl-sulfoxide is widely used as a solvent in pharmacological screening tests and has been shown to have heat shock induction effects. Transgenic Tg (hsp70l:EGFP-HRAS_G12V)io3(AB) zebrafish larvae were exposed for 24 hours to dimethyl-sulfoxide in concentratios of 0.1-2%, and to moderate heat shock inductors pentoxifylline and tacrolimus. Positive controls were exposed to 35, 38 and 40�C for 20 min, and incubated for 24 h at 28�C. Heat shock response was measured by fluorescence microscopy and signal intensity quantification in FIJI. Dimethyl-sulfoxide caused a dose-dependant increase in fluorescent intensity, but significantly lower compared with exposure to 38 and 40�C. Pentoxifylline and tacrolimus induced a significantly higher increase in fluorescence compared with 0.5% dimethyl-sulfoxide. Thus, although dimethyl-sulfoxide has independent heat shock induction effects, concentrations of up to 0.5% are suitable for heat shock response screening tests.

Download Full-text

Thiol reducing reagents inhibit the heat shock response. Involvement of a redox mechanism in the heat shock signal transduction pathway.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)43873-2 ◽

1994 ◽

Vol 269 (48) ◽

pp. 30718-30725

Author(s):

L E Huang ◽

H Zhang ◽

S W Bae ◽

A Y Liu

Keyword(s):

Signal Transduction ◽

Heat Shock ◽

Heat Shock Response ◽

Signal Transduction Pathway ◽

Transduction Pathway ◽

Redox Mechanism ◽

Shock Response

Download Full-text

581 Effects of acoustic immune priming with low-intensity focused ultrasound (LOFU) and trabectedin on a murine model of osteosarcoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0581 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A616-A616

Author(s):

Shannon Keisling

Keyword(s):

Radiation Therapy ◽

Heat Shock ◽

Combination Therapy ◽

Murine Model ◽

Heat Shock Response ◽

Cell Activation ◽

Pulmonary Metastases ◽

Lung Metastases ◽

Therapy Group ◽

Shock Response

BackgroundOsteosarcoma is the most common primary bone tumor and has a peak incidence in adolescence. The prognosis for recurrent and metastatic disease is poor and over one-third of patients with localized disease at presentation will recur after treatment with metastases. LOFU produces non-lethal, transient mechanical and thermal stress to cause protein misfolding, endoplasmic reticulum stress, and induction of the heat shock response (refs). Trabectedin is directly tumoricidal through inhibiting transcription and DNA repair, modulates the tumor microenvironment by selectively depleting M2 macrophages, and inhibits the transcription factor heat shock factor 1 (HSF1) (refs). We hypothesized that combination therapy would synergistically intensify the unfolded protein response and heat shock response to facilitate antigen presenting cell activation and efficient presentation to cytotoxic T cells. To examine this, experiments are being conducted to investigate the effect of LOFU in combination with trabectedin and/or radiation therapy (RT) in a murine model of osteosarcoma.MethodsPalpable (<5 mm) subcutaneous K7M2 murine osteosarcoma tumors in BALB/c mice were treated with a) LOFU, b) trabectedin (intravenous (IV) or intratumoral (IT)), c) LOFU + trabectedin, and d) radiation. Tumor growth (ANOVA (Kruskal-Wallis) with Dunn’s test for multiple comparisons), pulmonary metastases (Fisher’s exact test) and survival (Kaplan-Meier) were measured and analyzed in GraphPad Prism.ResultsMean tumor volume in the combination therapy group (428 mm3) was less than nontreated controls (887 mm3), LOFU alone (670 mm3), trabectedin alone (1218 mm3, p=0.0386). Radiation therapy resulted in complete ablation of the tumors. None of the combination therapy mice had grossly detectable lung metastases at time of death but metastases were present in the trabectedin only (20%), LOFU only (50%), and control (50%) groups (not statistically significant).ConclusionsCombination therapy with trabectedin and LOFU yielded smaller tumor size and fewer pulmonary metastases compared to individual therapies alone.

Download Full-text