H. Lavon, P. Matzner, A. Benbenishty, L. Sorski, E. Rossene, R

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Dexmedetomidine promotes metastasis in rodent models of breast, lung, and colon cancers H. Lavon, P. Matzner, A. Benbenishty, L. Sorski, E. Rossene, R. Haldar, E. Elbaz, J.P. Cata, V. Gottumukkala, S. Ben-Eliyahu British Journal of Anaesthesia Volume 120, Issue 1, Pages 188-196 (January 2018) DOI: 10.1016/j.bja.2017.11.004 Copyright © 2017 British Journal of Anaesthesia Terms and Conditions

Fig 1 Maintenance and radiolabelling of MADB 106, CT26, and 3LL tumour cells, and assessment of organ tumour retention. British Journal of Anaesthesia 2018 120, 188-196DOI: (10.1016/j.bja.2017.11.004) Copyright © 2017 British Journal of Anaesthesia Terms and Conditions

Fig 2 Dexmedetomidine dose-dependently elevated MADB106 lung tumour retention in both sexes. A) Dexmededetomidine (Dexmed) elevated lung tumour retention dose-dependently, yielding significant increase in LTR compared to control levels at doses of 5 μg·kg-1·hr-1 and higher, exerting a greater impact in females. Two-way ANOVA indicated a significant main effect for dose of Dexmed (F(4,91) =34.82, p<0.0001), for sex (F(1,91) =21.96, p<0.0001), and a significant interaction (F(4,91) =11.42, p<0.0001). N=44 females and 49 males. B) Female rats (n = 50) were injected with Dexmed at different time intervals (in hr) before MADB106 tumour cells injection (-48,-24,-12,-6 or -2 and simultaneously with it (0)). One-way ANOVA indicated significant group differences (F6,49 =41.231, p<0.0001), and Fischer's PLSD pair-wise comparisons indicated that Dexmed increased LTR significantly if administered at 0, 2, 6, & 12 hr before tumour injection (p<0.0001 for all), but not at 24, or 48 hr. ● indicates significant pair-wise difference from the respective control (vehicle) group (PLSD, p < 0.05). Data presented as mean (SEM). British Journal of Anaesthesia 2018 120, 188-196DOI: (10.1016/j.bja.2017.11.004) Copyright © 2017 British Journal of Anaesthesia Terms and Conditions

Fig 3 Dexmedetomidine affects MADB106 lung tumour retention via α2 -adrenoceptors, but not via α1 -adrenoceptors, and the effects are not mediated through hypothermia. A) Female rats (n=29) received either yohimbine (α2-adrenoceptor antagonist) or phenoxybenzamine (phenoxy; α1-adreneceptor antagonist) with or without dexmedetomidine (Dexmed) (10 μg·kg-1·hr-1), one-way ANOVA indicated significant group differences (F7,28 =8.718, p<0.0001). B) Dexmededetomidine similarly increased tumour retention in male rats (n=43) both under normothermia or hypothermia conditions. One-way ANOVA indicated significant group differences (F2,40 =18.193, p<0.0001), ▴ indicates a significant increase relative to the control vehicle group (PLSD, p < 0.05) ● indicates a significant increase from vehicle group (PLSD, p < 0.05). Data presented as mean (SEM). British Journal of Anaesthesia 2018 120, 188-196DOI: (10.1016/j.bja.2017.11.004) Copyright © 2017 British Journal of Anaesthesia Terms and Conditions

Fig 4 Dexmedetomidine does not attenuate the deleterious effects of wet-cage or surgery stress on MADB106 lung tumour retention, but does so at a low dose under restrainer stress. A) Wet Cage Both female and male rats (n=71, 84 respectively) were either subjected to wet-cage stress or maintained at their home cages (control). Three-way ANOVA indicated a significant main effect for the dose of dexmedetomidine (Dexmed) (F2,143 =14.826, p<0.0001) and for stress (F1,143 =22.154, p<0.0001), but no significant effect for sex and no interactions. Both wet-cage stress and Dexmed elevated tumour retention significantly. B) Restraint Male rats (n=75) were subjected to either restraint stress or maintained at their home cages. While restraint stress elevated tumour retention levels, a low dose of Dexmed (2.5 μg·kg-1·hr-1) abolished this effect (PLSD p=0.0077). Two-way ANOVA indicated a significant main effect for the dose of Dexmed (F3,56 =3.887, p=0.0136) and for stress (F1,56 =12.892, p=0.0007), with no interactions. C) Surgery Male rats (n=65) were subjected to either surgery or maintained at their home cages. Two-way ANOVA indicated a significant main effect of Dexmed (F3,46 =15.091, p<0.0001) and for surgery (F1,46 =10.13, p=0.0026) with a significant interaction (F3,46 =3.341, p=0.0272). Dexmed significantly elevated MADB106 lung tumour retention in the control groups from the dose of 5 μg·kg-1·hr-1, but in animals undergoing surgery only the highest dose of Dexmed (20 μg·kg-1·hr-1) affected tumour retention. Surgery had increased LTR.▴ indicates a significant increase in the vehicle group caused by stress. ● indicates significant pair-wise difference from the respective control (vehicle) group (PLSD, p < 0.05). Data presented as mean (SEM). British Journal of Anaesthesia 2018 120, 188-196DOI: (10.1016/j.bja.2017.11.004) Copyright © 2017 British Journal of Anaesthesia Terms and Conditions

Fig 5 Dexmedetomidine elevated tumour retention in various organs, depending on the delivery method of tumour cells in two animal models. A) ECA inoculation in rats Dexmedetomidine (Dexmed) elevated MADB106 tumour retention in the brain, liver, lung, kidney, and muscle in the context of surgery, F344 female rats (n=13). Two-way ANOVA indicated a significant main effect of Dexmed (F1,49 =28.861, p<0.0001) and a significant main effect of organ (F4,49 =35.985, p<0.0001). B) Intravenous inoculation in rats Dexmed did not elevate MADB106 tumour retention in the brain, but did so in the lungs, kidneys and muscle, F344 female rats (n=9). Two-way ANOVA Indicated significant main effect for Dexmed (F1,28 =21.905, p<0.0001) and for organ inspected (F3,28 =18.334, p<0.0001). C) ECA inoculation in mice Male C57BL/6 mice (n=15) were injected with 3LL tumour cells via the ECA. Two-way ANOVA indicated significant main effect for Dexmed dose (F2, 132 =25.680, p<0.0001) and for organ (F4, 132 =60.122, p<0.0001).● indicates significant pair-wise difference from the organ-specific control (vehicle) group (PLSD, p < 0.05). Data presented as mean (SEM). British Journal of Anaesthesia 2018 120, 188-196DOI: (10.1016/j.bja.2017.11.004) Copyright © 2017 British Journal of Anaesthesia Terms and Conditions

Fig 6 Dexmedetomidine elevated the number of metastases counted three weeks following tumour inoculation in two animal models. A) Male (n=45) and female F344 rats (n=53) lungs were counted for experimental metastasis retention. Two-way ANOVA indicated a significant main effect for dexmedetomidine (Dexmed) dose (F93,2 =5.002, p=0.0086), and no effects for sex nor an interaction. B) Female mice (n=39) livers were counted for experimental metastasis retention. One-way ANOVA indicated a significant effect for Dexmed (F2,36 =4.252, p=0.022). Dexmed elevated the number of liver metastasis significantly in both doses. ● indicates significant pair-wise difference from the vehicle control group (PLSD, p < 0.05). Data presented as mean (SEM). British Journal of Anaesthesia 2018 120, 188-196DOI: (10.1016/j.bja.2017.11.004) Copyright © 2017 British Journal of Anaesthesia Terms and Conditions