Delving into the Latest Updates on Tocladesine with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Adenazole, Tocladesine (USAN/INN)

+ [4]

Target

caspase 3

Mechanism

caspase 3 inhibitors(Caspase-3 inhibitors), Cyclic AMP agonists

Therapeutic Areas

NeoplasmsImmune System DiseasesCardiovascular Diseases+ [3]

Active Indication-

Inactive Indication

Colorectal CancerMetastatic Colorectal CarcinomaPlasma cell myeloma refractory+ [1]

Originator Organization

Bausch Health Cos., Inc.

Active Organization-

Inactive Organization

National Cancer Institute

Bausch Health Cos., Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC10H11ClN5O6P

InChIKeyCLLFEJLEDNXZNR-UUOKFMHZSA-N

CAS Registry41941-56-4

The oncogenic activation of the rearranged during transfection (RET) proto-oncogene has a main role in the pathogenesis of medullary thyroid cancer (MTC). Several lines of evidence suggest that RET function could be influenced by cyclic AMP (cAMP)-dependent protein kinase A (PKA) activity. We evaluated the in vitro anti-tumor activity of 8-chloroadenosine-3',5'-cyclic monophosphate (8-Cl-cAMP) and PKA type I-selective cAMP analogs [equimolar combination of the 8-piperidinoadenosine-3',5'-cyclic monophosphate (8-PIP-cAMP) and 8-hexylaminoadenosine-3',5'-cyclic monophosphate (8-HA-cAMP) in MTC cell lines (TT and MZ-CRC-1)]. 8-Cl-cAMP and the PKA I-selective cAMP analogs showed a potent anti-proliferative effect in both cell lines. In detail, 8-Cl-cAMP blocked significantly the transition of TT cell population from G2/M to G0/G1 phase and from G0/G1 to S phase and of MZ-CRC-1 cells from G0/G1 to S phase. Moreover, 8-Cl-cAMP induced apoptosis in both cell lines, as demonstrated by FACS analysis for annexin V-FITC/propidium iodide, the activation of caspase-3 and PARP cleavage. On the other hand, the only effect induced by PKA I-selective cAMP analogs was a delay in G0/G1-S and S-G2/M progression in TT and MZ-CRC-1 cells, respectively. In conclusion, these data demonstrate that cAMP analogs, particularly 8-Cl-cAMP, significantly suppress in vitro MTC proliferation and provide rationale for a potential clinical use of cAMP analogs in the treatment of advanced MTC.

01 Aug 2015·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

SHC1 sensitizes cancer cells to the 8-Cl-cAMP treatment

Q3 · BIOLOGY

Article

Author: Choi, Ki Young ; Kim, Jeong Seon ; Cho, Young Jun ; Hong, Seung Hwan ; Ahn, Young-Ho

8-Chloro-cyclic AMP (8-Cl-cAMP) is a cyclic AMP analog that induces growth inhibition and apoptosis in a broad spectrum of cancer cells. Previously, we found that 8-Cl-cAMP-induced growth inhibition is mediated by AMP-activated protein kinase (AMPK) as well as p38 mitogen-activated protein kinase (p38 MAPK). To identify downstream mediators of the 8-Cl-cAMP signaling, we performed co-immunoprecipitation combined with mass spectrometry using the anti-AMPK or p38 MAPK antibodies. Through this approach, SHC1 was identified as one of the binding partners of p38 MAPK. SHC1 phosphorylation was suppressed by 8-Cl-cAMP in HeLa and MCF7 cancer cells, which was mediated by its metabolites, 8-Cl-adenosine and 8-Cl-ATP; however, 8-Cl-cAMP showed no effect on SHC1 phosphorylation in normal human fibroblasts. SHC1 siRNA induced AMPK and p38 MAPK phosphorylation and growth inhibition in cancer cells, and SHC1 overexpression re-sensitized human foreskin fibroblasts to the 8-Cl-cAMP treatment. SHC1 phosphorylation was unaffected by Compound C (an AMPK inhibitor) and SB203580 (a p38 MAPK inhibitor), which suggests that SHC1 is upstream of AMPK and p38 MAPK in the 8-Cl-cAMP-stimulated signaling cascade. On the basis of these findings, we conclude that SHC1 functions as a sensor during the 8-Cl-cAMP-induced growth inhibition in SHC1-overexpressing cancer cells.

01 Jan 2012·Oncology LettersQ4 · MEDICINE

8-Chloroadenosine 3′,5′-monophosphate induces cell cycle arrest and apoptosis in multiple myeloma cells through multiple mechanisms

Q4 · MEDICINE

Article

Author: Li-Fang Zou ; Yong Tang ; Yi-Yun Yao ; Ming-Ming Wang ; Yi-Min Cheng ; Qi Zhu

The aim of this study was to investigate the molecular mechanism of 8-chloroadenosine 3',5'-monophosphate (8-Cl-cAMP) in the inhibition of the growth and induction of apoptosis of multiple myeloma (MM) cells. Two MM-derived cell lines, RPMI-8226 and U266, were used. Cell viability, apoptosis induction and mitochondrial transmembrane potential were determined and the expression levels of cell cycle regulatory proteins (Cdk2, cyclin E, p27 and c-myc) and p38 mitogen-activated protein kinase (MAPK) protein were detected. Following treatment with 8-Cl-cAMP, the percentage of apoptotic cells increased in a concentration- and time-dependent manner and the mitochondrial transmembrane potential collapsed to reveal typical apoptotic features. Our data further demonstrated that 8-Cl-cAMP induced progressive phosphorylation of p38 MAPK and that the expression levels of p27 proteins in the MM cells were increased whereas those of c-myc were significantly decreased. Notably, the proapoptotic effect of 8-Cl-cAMP was largely prevented by a p38 MAPK inhibitor. Furthermore, knockdown of p27 was able to decrease the 8-Cl-cAMP-induced apoptosis in the MM cells. These results indicate that 8-Cl-cAMP induced p27-dependent cell cycle arrest and apoptosis in the MM cells, which demonstrates the potential of cAMP-modulating agents for use in the treatment of MM.

100 Deals associated with Tocladesine

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External Link

KEGG	Wiki	ATC	Drug Bank
D06173	-	-	DB13046

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Metastatic Colorectal Carcinoma	Phase 2	US	National Cancer Institute	01 Apr 2001
Plasma cell myeloma refractory	Phase 2	US	National Cancer Institute	01 Jan 1998
Relapse multiple myeloma	Phase 2	US	National Cancer Institute	01 Jan 1998
Colorectal Cancer	Phase 2	US	-	-
Colorectal Cancer	Phase 2	-	National Cancer Institute	-
Colorectal Cancer	Phase 1	-	Bausch Health Cos., Inc.	-