BH3-Mimetic Drugs: Blazing the Trail for New Cancer Medicines

BCL-XL is essential for the protection from secondary anemia caused by radiation-induced fatal kidney damage

“…All mice recovered within ~10 days ( Figure 6C). This is consistent with the described BCL-XL-dependency of platelets and thus platelet toxicity followed by the rapid induction of a rebound production of platelets upon treatment with BCL-XL-inhibiting BH3 mimetic drugs (Leverson et al, 2015;Mason et al, 2007;Merino et al, 2018;Wilson et al, 2010). As reported (Brinkmann et al, 2017), treatment with 5-FU caused mild anemia ( Figure 6E), and mice that were treated with Cyclophosphamide showed a reduction in lymphocytes at day 6 posttreatment (Supplementary Figure S5D).…”

“…No adverse effects of any of these treatments were detected for at least 150 days ( Figure 6A, B). As expected (Leverson et al, 2015;Mason et al, 2007;Merino et al, 2018;Wilson et al, 2010), treatment with A1331852 resulted in on-target platelet toxicity at day 2 post-treatment, followed by high platelet counts at days 5-6 post treatment ( Figure 6C, G). All mice recovered within ~10 days ( Figure 6C).…”

“…BH3 mimetic drugs targeting select anti-apoptotic BCL-2-family members represent promising novel agents in cancer therapy (Merino et al, 2018). The BCL-XL-specific inhibitor A1331852 (Lessene et al, 2013) has not yet entered clinical trials, mostly due to its on-target toxicity in platelets that is also seen with ABT-263/navitoclax that inhibits BCL-XL, BCL-2 and BCL-W (Leverson et al, 2015;Mason et al, 2007;Wilson et al, 2010).…”

“…The BCL-XL-specific inhibitor A1331852 (Lessene et al, 2013) has not yet entered clinical trials, mostly due to its on-target toxicity in platelets that is also seen with ABT-263/navitoclax that inhibits BCL-XL, BCL-2 and BCL-W (Leverson et al, 2015;Mason et al, 2007;Wilson et al, 2010). Nevertheless, many cancers depend on BCL-XL for sustained growth (Campbell and Tait, 2018;Merino et al, 2018) and extensive work is being conducted to develop modes of administration and dose schedules for the safe use of BCL-XL inhibitors (Khan et al, 2019). Our present data indicate that the combination of BCL-XL inhibitors with DNA damage-inducing therapies might cause renal toxicity with secondary anemia.…”

“…Evasion of apoptotic cell death is a hallmark of cancer (Hanahan and Weinberg, 2000;Hanahan and Weinberg, 2011) and direct activation of the cell death machinery by BH3-mimetic drugs represents an attractive therapeutic strategy (Merino et al, 2018). Apoptosis is controlled by proand anti-apoptotic members of the BCL-2 protein family (Tait and Green, 2010), with the transcriptional or post-transcriptional activation of the pro-apoptotic BH3-only members of the BCL-2 family (e.g.…”