Novel Apoptosis-Inducing Agents for the Treatment of Cancer, a New Arsenal in the Toolbox

Greer, Yoshimi Endo; Lipkowitz, Stanley; Takebe, Naoko

doi:10.3390/cancers11081087

Cited by 53 publications

(41 citation statements)

References 307 publications

(377 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other, very often, mutations in cancer cells make them unable to deliver one or the other pathway [3]. Indeed, apoptosis inducers offer promises for achieving, in both normal and malignant cells, a decreased toxicity coupled with an improved therapeutic outcome [5,6].…”

Section: Introductionmentioning

confidence: 99%

Curcumin-1,2,3-Triazole Conjugation for Targeting the Cancer Apoptosis Machinery

et al. 2020

View full text Add to dashboard Cite

The burden of neoplastic diseases is widely recognized as a severe cause of mortality. The clinical inadequacy of most anticancer therapeutics urgently prompted intense drug discovery efforts toward the identification of new chemical entities endowed with a potent and safe antitumor profile. In this scenario, targeting cancer cells apoptosis machinery has emerged as a relevant strategy, useful for tackling the emergence of drug resistance. On this basis, a small library of naturally inspired hybrid molecules was obtained by combining, through a click chemistry approach, “privileged” synthons such as curcumin scaffold and 1,2,3-triazole building block. Compound 1, bearing a para-fluoro phenyl moiety, showed low-micromolar potency against T acute lymphoblastic leukemia cell growth. More in-depth biologic studies demonstrated, for this analog, cell death-inducing properties associated with its capability to simultaneously activate both the receptor and the mitochondrial apoptosis cascades. This peculiar behavior offers promises for achieving an expanded anticancer effect, namely intense cytotoxic response coupled with reduced predisposition of chemoresistance insurgence. Altogether, this study allowed the identification of compound 1 as a lead compound worth to be progressed as an anticancer drug candidate.

show abstract

Section: Introductionmentioning

confidence: 99%

Curcumin-1,2,3-Triazole Conjugation for Targeting the Cancer Apoptosis Machinery

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Because the gene encoding protein p53 is often mutated in cancers, TRAIL's ability to activate apoptosis independently of the p53, together with its tumor-selectivity, made TRAIL an attractive therapeutic target ( Elmore, 2007 ; Lim et al, 2019 ). Yet, owing to TRAIL's ability to bind to four TRAIL receptors with a similarly high affinity, the understanding of TRAIL signaling regulation represents a grand challenge ( Micheau et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

The TRAIL in the Treatment of Human Cancer: An Update on Clinical Trials

Snajdauf

Havlová

Vachtenheim³

et al. 2021

Front. Mol. Biosci.

100

View full text Add to dashboard Cite

TRAIL (tumor-necrosis factor related apoptosis-inducing ligand, CD253) and its death receptors TRAIL-R1 and TRAIL-R2 selectively trigger the apoptotic cell death in tumor cells. For that reason, TRAIL has been extensively studied as a target of cancer therapy. In spite of the promising preclinical observations, the TRAIL–based therapies in humans have certain limitations. The two main therapeutic approaches are based on either an administration of TRAIL-receptor (TRAIL-R) agonists or a recombinant TRAIL. These approaches, however, seem to elicit a limited therapeutic efficacy, and only a few drugs have entered the phase II clinical trials. To deliver TRAIL-based therapies with higher anti-tumor potential several novel TRAIL-derivates and modifications have been designed. These novel drugs are, however, mostly preclinical, and many problems continue to be unraveled. We have reviewed the current status of all TRAIL-based monotherapies and combination therapies that have reached phase II and phase III clinical trials in humans. We have also aimed to introduce all novel approaches of TRAIL utilization in cancer treatment and discussed the most promising drugs which are likely to enter clinical trials in humans. To date, different strategies were introduced in order to activate anti-tumor immune responses with the aim of achieving the highest efficacy and minimal toxicity.In this review, we discuss the most promising TRAIL-based clinical trials and their therapeutic strategies.

show abstract

“…Obatoclax, a synthetic derivative of bacterial prodiginines [21], is a clinically developed small-molecule pan-BCL-2 inhibitor that functions by blocking BH3-mediated binding of BH3-only proteins or BAX/BAK to antiapoptotic BCL-2, BCL-xL, and MCL-1, causing BAX/BAK activation to trigger apoptosis [22]. Phase I/II clinical trials have revealed the anticancer potential of Obatoclax as a single agent or in combination with other chemo-and radiation therapies [23][24][25]. Notably, given overexpression of antiapoptotic BCL-2 family members is closely linked to therapeutic resistance in cancer cells, Obatoclax has been demonstrated to facilitate drug sensitization of chemoresistant cells in both hematological [23] and solid tumors [26].…”

Section: Introductionmentioning

confidence: 99%

Obatoclax, a Pan-BCL-2 Inhibitor, Downregulates Survivin to Induce Apoptosis in Human Colorectal Carcinoma Cells Via Suppressing WNT/β-catenin Signaling

Huang

Chang

et al. 2020

IJMS

View full text Add to dashboard Cite

Colorectal cancer (CRC) is a highly prevailing cancer and the fourth leading cause of cancer mortality worldwide. Aberrant expression of antiapoptotic BCL-2 family proteins is closely linked to neoplastic progression and chemoresistance. Obatoclax is a clinically developed drug, which binds antiapoptotic BCL-2, BCL-xL, and MCL-1 for inhibition to elicit apoptosis. Survivin is an antiapoptotic protein, whose upregulation correlates with pathogenesis, therapeutic resistance, and poor prognosis in CRC. Herein, we provide the first evidence delineating the functional linkage between Obatoclax and survivin in the context of human CRC cells. In detail, Obatoclax was found to markedly downregulate survivin. This downregulation was mainly achieved via transcriptional repression, as Obatoclax lowered the levels of both survivin mRNA and promoter activity, while blocking proteasomal degradation failed to prevent survivin from downregulation by Obatoclax. Notably, ectopic survivin expression curtailed Obatoclax-induced apoptosis and cytotoxicity, confirming an essential role of survivin downregulation in Obatoclax-elicited anti-CRC effect. Moreover, Obatoclax was found to repress hyperactive WNT/β-catenin signaling activity commonly present in human CRC cells, and, markedly, ectopic expression of dominant-active β-catenin mutant rescued the levels of survivin along with elevated cell viability. We further revealed that, depending on the cell context, Obatoclax suppresses WNT/β-catenin signaling in HCT 116 cells likely via inducing β-catenin destabilization, or by downregulating LEF1 in DLD-1 cells. Collectively, we for the first time define survivin downregulation as a novel, pro-apoptotic mechanism of Obatoclax as a consequence of Obatocalx acting as an antagonist to WNT/β-catenin signaling.

show abstract

Novel Apoptosis-Inducing Agents for the Treatment of Cancer, a New Arsenal in the Toolbox

Cited by 53 publications

References 307 publications

Curcumin-1,2,3-Triazole Conjugation for Targeting the Cancer Apoptosis Machinery

Curcumin-1,2,3-Triazole Conjugation for Targeting the Cancer Apoptosis Machinery

The TRAIL in the Treatment of Human Cancer: An Update on Clinical Trials

Obatoclax, a Pan-BCL-2 Inhibitor, Downregulates Survivin to Induce Apoptosis in Human Colorectal Carcinoma Cells Via Suppressing WNT/β-catenin Signaling

Contact Info

Product

Resources

About