Antimyeloma Effects of the Heat Shock Protein 70 Molecular Chaperone Inhibitor MAL3-101

Figure 6

Effect of MAL3-101 and PS-341 on myeloma cell growth in vivo. (A) shows repeated measures as condition effect in NSG mice which were inoculated subcutaneously in the right flank with 3×10⁷ NCI-H929 cells. Mice received 40 mg/kg MAL3-101, 1 mg/kg PS-341, a combination of these agents, or the vehicle twice weekly i.p. (𝑛=16). Tumor volume assessments were performed on indicated days. Overall repeated measures by treatment condition were observed (𝐹(15,50)=4.89; 𝑃=0.00001), and MAL3-101 and PS-341 each delayed tumor growth over 20 days from initial treatment; however, in combination, MAL3­101 and PS-341 had a greater effect than the single treatments by delaying tumor progression and reducing tumor size. Vertical bars denote 0.95 confidence interval. a–e refer to results of ANOVAs for effect of treatment by day on tumor inhibition. (a) Overall condition effect on day 6: 𝐹(3,10)=5.40; 𝑃=0.018; Tukey HSD: vehicle > MAL3-101 and PS-341 combination. (b) Overall condition effect on day 9: 𝐹(3,10)=5.25; 𝑃=0.02; Tukey HSD: vehicle > MAL3-101 and PS-341 combination. (c) Overall condition effect on day 13: 𝐹(3,10)=10.57; 𝑃=0.002; Tukey HSD: vehicle > MAL3-101 and PS-341 combination; vehicle > PS-341. (d) Overall condition effect on day 16: 𝐹(3,10)=8.16; 𝑃=0.004; Tukey HSD: vehicle > MAL3­-101 and PS-341 combination; vehicle > PS-341. (e) Overall condition effect on day 20: 𝐹(3,10)=7.33; 𝑃=0.01; Tukey HSD: vehicle > MAL3­-101 and PS-341 combination; vehicle > PS-341. (B) The bar graph shows the computed mean percentage difference for each treatment versus vehicle. An overall condition effect was noted (𝐹(2,7)=10.25; 𝑃=0.008). Treatment with combination of PS-341 and MAL3-101 was significantly more effective on percent tumor inhibition in comparison to PS-341 or MAL3-101 alone (Tukey’s HSD test, 𝑃=0.02; 𝑃=0.008, resp.), although each individual treatment was not significantly different from each other. *indicates statistical significance. Vertical bars denote 0.95 confidence interval.