Expression of executioner procaspases and their activation by a procaspase-activating compound in chronic lymphocytic leukemia cells

Patel, Viralkumar; Balakrishnan, Kumudha; Keating, Michael J.; Wierda, William G.; Gandhi, Varsha

doi:10.1182/blood-2014-01-546796

Cited by 28 publications

(57 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…18 These results are consistent with the known modest affinity of PAC-1 for zinc, 36 allowing for a high degree of selectivity for chelation of zinc ions from the labile pool over essential zinc ions in canonical zinc binding sites within metalloproteins. In addition, PAC-1 is stable in aqueous solution; degradation of PAC-1 is observed only when the compound is subjected to extremes in temperature and pH outside of relevant physiological ranges.…”

Section: Introductionsupporting

confidence: 79%

See 1 more Smart Citation

Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics

et al. 2015

View full text Add to dashboard Cite

Procaspase-Activating Compound 1 (PAC-1) is an ortho-hydroxy-N-acylhydrazone that induces apoptosis in cancer cells by chelation of labile inhibitory zinc from procaspase-3. PAC-1 has been assessed in a wide variety of cell culture experiments and in vivo models of cancer, with promising results, and a Phase 1 clinical trial in cancer patients has been initiated (NCT02355535). For certain applications, however, the in vivo half-life of PAC-1 could be limiting. Thus, with the goal of developing a compound with enhanced metabolic stability, a series of PAC-1 analogues was designed containing modifications that systematically block sites of metabolic vulnerability. Evaluation of the library of compounds identified four potentially superior candidates with comparable anticancer activity in cell culture, enhanced metabolic stability in liver microsomes, and improved tolerability in mice. In head-to-head experiments with PAC-1, pharmacokinetic evaluation in mice demonstrated extended elimination half-lives and greater AUC values for each of the four compounds, suggesting them as promising candidates for further development.

show abstract

Section: Introductionsupporting

confidence: 79%

“…67, 68 Because of this unique mechanism, PAC-1 is increasingly being used as a tool to directly activate procaspase-3 in a variety of biological settings. 66, 67, 69, 70 In addition, PAC-1 and derivatives have shown synergy with experimental therapeutics 18, 48 and with the anticancer drug paclitaxel. 55 …”

Section: Introductionmentioning

confidence: 99%

Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Consistent with this statement, in biochemical assay systems, B-PAC-1 did not alter the activity of other zinc-dependent enzyme such as carboxypeptidase A and HDAC [26]. Similarly, inflammatory procaspase (procaspase-1) was not affected by B-PAC-1 [26].…”

Section: Discussionmentioning

confidence: 67%

“…B-PAC-1 chelates zinc ions specifically from procaspase-3 and other executioner procaspases, thereby activating apoptosis [26]. Consistent with this statement, in biochemical assay systems, B-PAC-1 did not alter the activity of other zinc-dependent enzyme such as carboxypeptidase A and HDAC [26].…”

Section: Discussionmentioning

confidence: 76%

See 1 more Smart Citation

Targeting executioner procaspase-3 with the procaspase-activating compound B-PAC-1 induces apoptosis in multiple myeloma cells

Zaman

Wang

Gandhi

2015

Experimental Hematology

Self Cite

View full text Add to dashboard Cite

Multiple myeloma (MM) is a plasma cell neoplasm that has a low apoptotic index. We investigated a new class of small molecules that target the terminal apoptosis pathway, called procaspase activating compounds (PACs), in myeloma cells. PAC agents (PAC-1 and B-PAC-1) convert executioner procaspases (procaspase-3, -6 and -7) to active caspase-3, -6, and -7, which cleave target substrates to induce cellular apoptosis cascade. We hypothesized that targeting this terminal step will overcome survival and drug-resistance signals in myeloma cells and induce programmed cell death. Myeloma cells expressed executioner caspases. In concert, our studies demonstrated that B-PAC-1 is cytotoxic to chemotherapy resistant or sensitive myeloma cell lines (n=7) and primary patient cells (n=11). Exogenous zinc abrogated B-PAC-1-induced cell demise. B-PAC-1-treatment-induced apoptosis was similar in the presence or absence of growth-promoting cytokines such as interleukin-6 and hepatocyte growth factor. Presence or absence of anti-apoptotic proteins such as BCL-2, BCL-XL, or MCL-1 did not impact B-PAC-1-mediated programmed cell death. Collectively, our data demonstrate the proapoptotic effect of B-PAC-1 in MM and suggests that activating terminal executioner procaspase-3, -6 and -7 bypasses survival and drug-resistance signals in myeloma cells. This novel strategy has the potential to be an effective anti-myeloma therapy.

show abstract

Developing Ligands to Target Transition Metals in Cancer

Utterback

Tomat

2019

Encyclopedia of Inorganic and Bioinorganic Chemistry

View full text Add to dashboard Cite

Transition metals are essential for the function for numerous metalloproteins and cofactors in living systems. Their acquisition, transport, and storage are tightly regulated and the homeostasis of redox‐active cations such as iron and copper is especially critical to prevent the damaging effects of oxidative stress. Indeed the dyshomeostasis of metals has been observed in the pathophysiology of several diseases, and multiple metal‐binding compounds are currently under investigation as therapeutic candidates. Herein, we focus on the altered metal metabolisms of malignant cells and on metal‐binding strategies for the design of cancer chemotherapeutics. Iron, copper, and zinc chelators with a variety of binding motifs have been studied for their antiproliferative effects in malignant cells, and several compounds have reached clinical trials. Recent pro‐chelation approaches, in which the chelator is activated under specific conditions, are poised to increase therapeutic indexes and avoid unwanted side effects. As additional information emerges on the roles of metals in cancer biology, the design of metal‐binding drug candidates is evolving to improve their selectivity and efficacy and to consider their effects on the immune cells present in the tumor microenvironment. In addition, extensive studies to develop inhibitors of metalloenzymes relevant to cancer growth have led to several new anticancer therapeutics that coordinate the zinc centers in the active site of the enzymes. As illustrated by the examples collected herein, approaches that target either labile or protein‐bound transition metals have significant potential to produce new therapeutic options for cancer treatment.

show abstract

Expression of executioner procaspases and their activation by a procaspase-activating compound in chronic lymphocytic leukemia cells

Abstract: Key Points Pharmacologic activation of executioner procaspases by B-PAC-1 in CLL bypasses antiapoptotic mechanisms and induces apoptosis. B-PAC-1 activates apoptosis by abrogating the zinc ion-dependent inhibition of executioner procaspase activation.

Cited by 28 publications

References 40 publications

Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics

Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics

Targeting executioner procaspase-3 with the procaspase-activating compound B-PAC-1 induces apoptosis in multiple myeloma cells

Developing Ligands to Target Transition Metals in Cancer

Contact Info

Product

Resources

About