A Phase II Open-Label Extension Study of the Safety and Efficacy of Atiprimod Treatment for Patients With Low to Intermediate Grade Neuroendocrine Carcinoma

This study is an extension study to the Callisto protocol CP-106. Subjects must have completed all 12 treatment cycles of CP-106 without disease progression as per RECIST criteria,to be eligible to to be enrolled in this study. This study will evaluate the safety and efficacy of atiprimod treatment in patients with low to intermediate grade neuroendocrine carcinoma who have metastatic or unresectable local-regional cancer and who have either symptoms (diarrhea, flushing and/or wheezing) despite standard therapy (octreotide) or progression of neuroendocrine tumor(s).

Start Date01 Nov 2007

Sponsor / Collaborator

Callisto Pharmaceuticals, Inc.

NCT00388063 / CompletedPhase 2

A Phase II Open-Label Study of the Safety and Efficacy of Atiprimod Treatment for Patients With Low to Intermediate Grade Neuroendocrine Carcinoma

This study will evaluate the safety and efficacy of atiprimod treatment in patients with low to intermediate grade neuroendocrine carcinoma who have metastatic or unresectable local-regional cancer and who have either symptoms (diarrhea, flushing and/or wheezing) despite standard therapy (octreotide) or progression of neuroendocrine tumor(s).

Start Date01 Oct 2006

Sponsor / Collaborator

Callisto Pharmaceuticals, Inc.

NCT00430014 / TerminatedPhase 1IIT

An Open-Label Study of the Safety and Efficacy of Atiprimod Treatment for Patients With Advanced Cancer

Primary Objectives:
The primary objectives of this study are to identify the maximum tolerated dose (MTD) and to evaluate the safety of atiprimod when given in doses starting at 60 mg/day and ranging to 360 mg/day, or the MTD, whichever is lower, in patients with advanced cancer.
Secondary Objectives:
The secondary objectives of this study are to measure the pharmacokinetics of atiprimod and to evaluate the efficacy of atiprimod treatment in patients with advanced cancer, and to compare the pharmacokinetics of atiprimod tablets and capsules at the starting dose, with the intent of switching to capsules for the dose escalation if the capsules pose no safety issues.

Start Date01 Mar 2005

Sponsor / Collaborator

The University of Texas MD Anderson Cancer Center

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100 Clinical Results associated with Atiprimod dihydrochloride

100 Translational Medicine associated with Atiprimod dihydrochloride

100 Patents (Medical) associated with Atiprimod dihydrochloride

Literatures (Medical) associated with Atiprimod dihydrochloride

01 Jun 2021·Molecular Biology ReportsQ4 · BIOLOGY

Atiprimod triggered apoptotic cell death via acting on PERK/eIF2α/ATF4/CHOP and STAT3/NF-ΚB axis in MDA-MB-231 and MDA-MB-468 breast cancer cells

Q4 · BIOLOGY

Article

Author: Sahin, Semanur ; Arisan, Elif-Damla ; Obakan-Yerlikaya, Pınar ; Coker-Gurkan, Ajda ; Can, Esin

PURPOSEThe constitutive activation of STAT3 through receptor tyrosine kinases triggered breast cancer cell growth and invasion-metastasis. Atiprimod impacts anti-proliferative, anti-carcinogenic effects in hepatocellular carcinoma, lymphoma, multiple myeloma via hindering the biological activity of STAT3. Dose-dependent atiprimod evokes first autophagy as a survival mechanism and then apoptosis due to prolonged ER stress in pituitary adenoma cells. The therapeutic efficiency and mechanistic action of atiprimod in breast cancer cells have not been investigated yet. Thus, we aimed to modulate the pivotal role of ER stress in atiprimod-triggered apoptosis in MDA-MB-231 and MDA-MB-468 breast cancer cells.RESULTSDose- and time-dependent atiprimod treatment inhibits cell viability and colony formation in MDA-MB-468 and MDA-MB-231 breast cancer cells. A moderate dose of atiprimod (2 μM) inhibited STAT3 phosphorylation at Tyr705 residue and also suppressed the total expression level of p65. In addition, nuclear localization of STAT1, 3, and NF-κB was prevented by atiprimod exposure in MDA-MB-231 and MDA-MB-468 cells. Atiprimod evokes PERK, BiP, ATF-4, CHOP upregulation, and PERK (Thr980), eIF2α (Ser51) phosphorylation's. However, atiprimod suppressed IRE1α-mediated Atg-3, 5, 7, 12 protein expressions and no alteration was observed on Beclin-1, p62 expression levels. PERK/eIF2α/ATF4/CHOP axis pivotal role in atiprimod-mediated G1/S arrest and apoptosis via Bak, Bax, Bim, and PUMA upregulation in MDA-MB-468 cells. Moreover, atiprimod renders MDA-MB-231 more vulnerable to type I programmed cell death by plasmid-mediated increased STAT3 expression.CONCLUSIONAtiprimod induced prolonged ER stress-mediated apoptosis via both activating PERK/eIF2α/ATF4/CHOP axis and suppressing STAT3/NF-κB transcription factors nuclear migration in TBNC cells.

01 Nov 2020·Molecular Biology ReportsQ4 · BIOLOGY

Proinflammatory cytokine profile is critical in autocrine GH-triggered curcumin resistance engulf by atiprimod cotreatment in MCF-7 and MDA-MB-231 breast cancer cells

Q4 · BIOLOGY

Article

Author: Ozakaltun, Buse ; Arisan, Elif-Damla ; Akkoc, Tunc ; Coker-Gurkan, Ajda ; Akdeniz, Berre-Serra ; Obakan-Yerlikaya, Pınar ; Ergen, Berfin

Active growth hormone (GH) signaling triggers cellular growth and invasion-metastasis in colon, breast, and prostate cancer. Curcumin, an inhibitor of NF-ҡB pathway, is assumed to be a promising anti-carcinogenic agent. Atiprimod is also an anti-inflammatory, anti-carcinogenic agent that induces apoptotic cell death in hepatocellular carcinoma, multiple myeloma, and pituitary adenoma. We aimed to demonstrate the potential additional effect of atiprimod on curcumin-induced apoptotic cell death via cytokine expression profiles in MCF-7 and MDA-MB-231 cells with active GH signaling. The effect of curcumin and/or atiprimod on IL-2, IL-4, and IL-17A levels were measured by ELISA assay. MTT cell viability, trypan blue exclusion, and colony formation assays were performed to determine the effect of combined drug exposure on cell viability, growth, and colony formation, respectively. Alteration of the NF-ҡB signaling pathway protein expression profile was determined following curcumin and/or atiprimod exposure by RT-PCR and immunoblotting. Finally, the effect of curcumin with/without atiprimod treatment on Reactive Oxygen Species (ROS) generation and apoptotic cell death was examined by DCFH-DA and Annexin V/PI FACS flow analysis, respectively. Autocrine GH-mediated IL-6, IL-8, IL-10 expressions were downregulated by curcumin treatment. Atiprimod co-treatment increased the inhibitory effect of curcumin on cell viability, proliferation and also increased the curcumin-triggered ROS generation in each GH⁺ breast cancer cells. Combined drug exposure increased apoptotic cell death through acting on IL-2, IL-4, and IL-17A secretion. Forced GH-triggered curcumin resistance might be overwhelmed by atiprimod and curcumin co-treatment via modulating NF-ҡB-mediated inflammatory cytokine expression in MCF-7 and MDA-MB-231 cells.

01 Dec 2019·Journal of Cellular BiochemistryQ3 · BIOLOGY

Atiprimod induce apoptosis in pituitary adenoma: Endoplasmic reticulum stress and autophagy pathways

Q3 · BIOLOGY

Article

Author: Ayhan‐Sahin, Burcu ; Obakan‐Yerlikaya, Pınar ; Palavan‐Unsal, Narcin ; Coker‐Gurkan, Ajda ; Arisan, Elif‐Damla ; Keceloglu, Gizem

AbstractPituitary adenoma is the most common tumor with a high recurrence rate due to a hormone‐dependent JAK/signal transducer and activator of transcriptions (STAT) signaling. Atiprimod, a novel compound belonging to the azaspirane class of cationic amphiphilic drugs, has antiproliferative, anticarcinogenic effects in multiple myeloma, breast, and hepatocellular carcinoma by blocking STAT3 activation. Therapeutic agents' efficiency depends on endoplasmic reticulum (ER) stress‐autophagy regulation during drug‐mediated apoptotic cell death decision. However, the molecular machinery of dose‐dependent atiprimod treatment regarding ER stress‐autophagy has not been investigated yet. Thus, our aim is to investigate the ER stress‐autophagy axis in atiprimod‐mediated apoptotic cell death in GH‐secreting rat cell line (GH3) pituitary adenoma cells. Dose‐dependent atiprimod treatment decreased GH3 cell viability, inhibited cell growth, and colony formation. Upregulation of Atg5, Atg12, Beclin‐1 expressions, cleavage of LC‐3II and formation of autophagy vacuoles were determined only after 1 µM atiprimod exposure. In addition, atiprimod‐triggered ER stress was evaluated by BiP, C/EBP‐homologous protein (CHOP), p‐PERK upregulation, and Ca+2 release after 1 µM atiprimod exposure. Concomitantly, increasing concentration of atiprimod induced caspase‐dependent apoptotic cell death via modulating Bcl2 family members. Moreover, by N‐acetyl cycteinc pretreatment, atiprimod triggered reactive oxygen species generation and prevented apoptotic induction. Concomitantly, dose‐dependent atiprimod treatment decreased both GH and STAT3 expression in GH3 cells. In addition, overexpression of STAT3 increased atiprimod‐mediated cell viability loss and apoptotic cell death through suppressing autophagy and ER stress key molecules expression profile. In conclusion, a low dose of atiprimod exposure triggers autophagy and mild‐ER stress as a survival mechanism, but increased atiprimod dose induced caspase‐dependent apoptotic cell death by targeting STAT3 in GH3 pituitary adenoma cells.

News (Medical) associated with Atiprimod dihydrochloride

15 May 2007

·www.biospace.com

Callisto Pharmaceuticals Announces Article Citing Atiprimod in Major Scientific News Journal

NEW YORK, May 15 /PRNewswire-FirstCall/ -- Callisto Pharmaceuticals, Inc. , a biopharmaceutical company focused on the development of new drugs to treat cancer and inflammatory diseases, announced today that an article citing the history of its anti-cancer drug Atiprimod appeared in Genetic Engineering & Biotechnology News (GEN) (May 1, 2007). Genetic Engineering & Biotechnology News (GEN), the only high-frequency publication dedicated to biotech news, was introduced in 1981, as the first biotechnology trade publication. GEN is now the most widely read bionews publication worldwide. You may read the article at the following URL. The article in print also has a Figure image describing the mechanism of action of atiprimod. The article is available on the Genetic Engineering & Biotechnology News website at . About Callisto Pharmaceuticals, Inc. Callisto is a biopharmaceutical company focused on the development of new drugs to treat various forms of cancer and other serious afflictions. Callisto's drug candidates in development currently include anti-cancer agents in clinical development, in addition to drugs in pre-clinical development for other significant health care markets, including ulcerative colitis. One of the Company's lead drug candidates, Atiprimod, is in development to treat advanced carcinoid cancer, a neuroendocrine tumor, and in relapsed or refractory multiple myeloma, a blood cancer. Atiprimod is currently in a Phase II clinical trial in advanced carcinoid cancer patients, and in Phase I/IIa human clinical trials in relapsed or refractory multiple myeloma patients, respectively. A second anti-cancer drug, L-Annamycin, is being developed as a treatment for forms of relapsed or refractory acute leukemia, a currently incurable blood cancer. L-Annamycin, a new compound from the anthracycline family of proven anti-cancer drugs, has a novel therapeutic profile, including activity against resistant diseases and significantly reduced cardiotoxicity, or damage to the heart, compared to currently available drug alternatives. Callisto also has drugs in preclinical development for gastro-intestinal inflammation, and cancer. Guanilib is the lead candidate of our Guanylate Cyclase Receptor Agonist (GCRA) platform. Callisto own worldwide patent coverage for therapeutic applications of Guanilib in cancer and GI inflammatory diseases. Guanilib is expected to enter clinical trial in inflammatory bowel disease in 2008. Callisto has exclusive worldwide licenses from AnorMED Inc. and M.D. Anderson Cancer Center to develop, manufacture, use and sell Atiprimod and L-Annamycin, respectively. Callisto is also listed on the Frankfurt Stock Exchange under the ticker symbol CA4. More information is available at . Forward-Looking Statements Certain statements made in this press release are forward-looking. Such statements are indicated by words such as "expect," "should," "anticipate" and similar words indicating uncertainty in facts and figures. Although Callisto believes that the expectations reflected in such forward-looking statements are reasonable, it can give no assurance that such expectations reflected in such forward-looking statements will prove to be correct. As discussed in the Callisto Pharmaceuticals Form S-3/A declared effective on February 15, 2007, and its periodic reports, as filed with the Securities and Exchange Commission, actual results could differ materially from those projected in the forward-looking statements as a result of the following factors, among others: uncertainties associated with product development, the risk that products that appeared promising in early clinical trials do not demonstrate efficacy in larger-scale clinical trials, the risk that Callisto will not obtain approval to market its products, the risks associated with dependence upon key personnel and the need for additional financing. Callisto Pharmaceuticals, Inc. CONTACT: Dan D'Agostino of Callisto Pharmaceuticals, Inc.,+1-212-297-0010, ext. 227, or dagostino@callistopharma.com Web site:

05 Jun 2006

·www.biospace.com

Callisto Pharmaceuticals Announces Additional Atiprimod Data From Phase I Clinical Trial In Advanced Cancer Patients

NEW YORK--(BUSINESS WIRE)--June 2, 2006--Callisto Pharmaceuticals, Inc. (AMEX:KAL - News; FWB:CA4), a developer of new drug treatments in the fight against cancer and other major health threats, announced today a further update on the clinical data from a Phase I study of the safety and efficacy of Atiprimod, a novel azaspirane, for patients with advanced cancer. The trial, conducted at M.D. Anderson Cancer Center is an ongoing, single-center, open label, ascending dose Phase I trial of oral Atiprimod in patients with advanced cancer. Atiprimod was given by single dose orally for 14 days of every 28-day cycle.

100 Deals associated with Atiprimod dihydrochloride

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KEGG	Wiki	ATC	Drug Bank
D03003	Atiprimod dihydrochloride	-	DB05513

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Relapse multiple myeloma	Phase 3	US	Callisto Pharmaceuticals, Inc.	01 May 2004
Osteoarthritis	Phase 3	-	Callisto SAS	-
Osteoarthritis	Phase 3	-	GSK Plc	-
Rheumatoid Arthritis	Phase 3	-	Genzyme Corp.	-
Rheumatoid Arthritis	Phase 3	-	Callisto SAS	-
Rheumatoid Arthritis	Phase 3	-	GSK Plc	-
Multiple Myeloma	Phase 2	-	Callisto SAS	-
Multiple Myeloma	Phase 2	-	Genzyme Corp.	-
Multiple Myeloma	Phase 2	-	GSK Plc	-
Osteoarthritis	Phase 2	-	Genzyme Corp.	-

Clinical Result

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2008	Phase 2	Advanced Neuroendocrine Carcinoma	23	Atiprimod	(uozrerxyxy) = mejljvsrjr lfwjrtnboo (htpmiutbnu )	-	20 May 2008

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