Thymic Immunosuppressive Pentapeptide (TIPP) Showed Anticancer Activity in Breast Cancer and Chronic Myeloid Leukemia Both In Vitro and In Vivo

2021 ◽  
Vol 28 ◽  
Author(s):  
Muhammad Ijaz ◽  
Muhammad Shahbaz ◽  
Wenjie Jiang ◽  
Yikang Shi ◽  
Xiuli Guo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Chronic Myeloid Leukemia ◽  
Anticancer Activity ◽  
Myeloid Leukemia ◽  
Map Kinases ◽  
Inflammatory Responses ◽  
Tumor Xenograft ◽  
Immunohistochemistry Analysis

Aim: Being the common cause and major burden of deaths globally, timely management of cancer is crucial. Background: Thymic immunosuppressive pentapeptide (TIPP) is a novel pentapeptide originally obtained from calf thymic immunosuppressive extract. Previously, TIPP has been proved to suppress the allergic and inflammatory responses in allergic mice via blocking MAP kinases/NF-κB signaling pathways. Objective: In this study, in vitro anticancer activity of TIPP was tested on two different types of cancers using MCF-7 and K562 cell lines. Methods: Tumor xenograft models for breast cancer and chronic myeloid leukemia were designed. In vivo anticancer activity of TIPP was investigated on both cancer types. The liver and tumor tissues of the mice were preserved for immunohistochemistry analysis. Results: In vitro anticancer activity of TIPP showed significant inhibition on cell viability of both breast cancer and chronic myeloid leukemia. In vivo anticancer effect of TIPP in both types of cancer models further proved the potent anticancer nature of TIPP. Immunohistochemistry analysis assured that TIPP is a safe drug for normal organs such as the liver. Conclusion: Our present study revealed that TIPP is a potent anticancer drug and an important treatment option for various diseases. Further work is needed to test the flexible and proficient activity of the novel peptide.

scholarly journals Anticancer Activity of Triazolo-Thiadiazole Derivatives and Inhibition of AKT1 and AKT2 Activation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 493
Author(s):  
Dimitrios T. Trafalis ◽  
Sofia Sagredou ◽  
Panayiotis Dalezis ◽  
Maria Voura ◽  
Stella Fountoulaki ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Human Colon ◽  
Tumor Xenograft ◽  
Atp Binding Site ◽  
Anticancer Properties ◽  
Extensive Range ◽  
Dependent Inhibition ◽  
Ht 29

The fusion of 1,2,4-triazole and 1,3,4-thiadiazole rings results in a class of heterocycles compounds with an extensive range of pharmacological properties. A series of 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles was synthesized and tested for its enzyme inhibition potential and anticancer activity. The results show that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles display potent anticancer properties in vitro against a panel of cancer cells and in vivo efficacy in HT-29 human colon tumor xenograft in CB17 severe combined immunodeficient (SCID) mice. Preliminary mechanistic studies revealed that KA25 and KA39 exhibit time- and concentration-dependent inhibition of Akt Ser-473 phosphorylation. Molecular modeling experiments indicated that 1,2,4-triazolo[3,4-b]-1,2,4-thiadiazoles bind well to the ATP binding site in Akt1 and Akt2. The low acute toxicity combined with in vitro and in vivo anticancer activity render triazolo[3,4-b]thiadiazoles KA25, KA26, and KA39 promising cancer therapeutic agents.

scholarly journals Potentially Curative Therapeutic Activity of NEO212, a Perillyl Alcohol-Temozolomide Conjugate, in Preclinical Cytarabine-Resistant Models of Acute Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3385
Author(s):  
Axel H. Schönthal ◽  
Steve Swenson ◽  
Radu O. Minea ◽  
Hye Na Kim ◽  
Heeyeon Cho ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Side Effects ◽  
Anticancer Activity ◽  
Myeloid Leukemia ◽  
Perillyl Alcohol ◽  
Therapeutic Activity ◽  
Acute Myeloid

Despite progress in the treatment of acute myeloid leukemia (AML), the clinical outcome remains suboptimal and many patients are still dying from this disease. First-line treatment consists of chemotherapy, which typically includes cytarabine (AraC), either alone or in combination with anthracyclines, but drug resistance can develop and significantly worsen prognosis. Better treatments are needed. We are developing a novel anticancer compound, NEO212, that was created by covalent conjugation of two different molecules with already established anticancer activity, the alkylating agent temozolomide (TMZ) and the natural monoterpene perillyl alcohol (POH). We investigated the anticancer activity of NEO212 in several in vitro and in vivo models of AML. Human HL60 and U937 AML cell lines, as well as different AraC-resistant AML cell lines, were treated with NEO212 and effects on cell proliferation, cell cycle, and cell death were investigated. Mice with implanted AraC-sensitive or AraC-resistant AML cells were dosed with oral NEO212, and animal survival was monitored. Our in vitro experiments show that treatment of cells with NEO212 results in growth inhibition via potent G2 arrest, which is followed by apoptotic cell death. Intriguingly, NEO212 was equally potent in highly AraC-resistant cells. In vivo, NEO212 treatment strikingly extended survival of AML mice and the majority of treated mice continued to thrive and survive without any signs of illness. At the same time, we were unable to detect toxic side effects of NEO212 treatment. All in all, the absence of side effects, combined with striking therapeutic activity even in an AraC-resistant context, suggests that NEO212 should be developed further toward clinical testing.

scholarly journals Enhanced Anticancer Activity of Nanoformulation of Dasatinib against Triple-Negative Breast Cancer by Reduced Metabolic Degradation

2021 ◽  
Author(s):  
Fatemah Bahman ◽  
Valeria Pittalà ◽  
Mohamed Haider ◽  
Khaled Greish
Keyword(s):  
Breast Cancer ◽  
Anticancer Activity ◽  
Triple Negative Breast Cancer ◽  
Tyrosine Kinases ◽  
Triple Negative ◽  
Growth Factor Receptor ◽  
Initial Response ◽  
Response To Chemotherapy

Triple negative breast cancer (TNBC) is the most aggressive breast cancer accounting for around 15% of identified breast cancer cases. TNBC, by lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is unresponsive to current targeted therapies. Existing treatment relies on chemotherapeutic treatment but, despite an initial response to chemotherapy, the inception of resistance and relapse is unfortunately common. Dasatinib is an approved second-generation inhibitor of multiple tyrosine kinases and literature data strongly support its use in the management of TNBC. However, dasatinib binds to plasma proteins and undergoes extensive metabolism through oxidation and conjugation. To protect dasatinib from fast pharmacokinetic degradation and to prolong its activity, it was encapsulated on poly(styrene-co-maleic acid) (SMA) micelles. The obtained SMA-dasatinib nanoparticles (NPs) were evaluated for their physicochemical properties, in vitro antiproliferative activity in different TNBC cell lines, and in vivo anticancer activity in a syngeneic model of breast cancer. Obtained results showed that SMA-dasatinib is more potent against 4T1 TNBC tumor growth in vivo compared to free drug. This enhanced effect was ascribed to the encapsulation of the drug protecting it from a rapid metabolism. Our finding highlights the often-overlooked value of nanoformulations in protecting its cargo from degradation. Overall, results may provide an alternative therapeutic strategy for TNBC management.

siRNA/lipopolymer nanoparticles to arrest growth of chronic myeloid leukemia cells in vitro and in vivo

2018 ◽  
Vol 130 ◽  
pp. 66-70 ◽  
Author(s):  
Juliana Valencia-Serna ◽  
Hamidreza M. Aliabadi ◽  
Adam Manfrin ◽  
Mahsa Mohseni ◽  
Xiaoyan Jiang ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Arrest Growth

scholarly journals Detection of breakpoint cluster region- negative and nonclonal hematopoiesis in vitro and in vivo after transplantation of cells selected in cultures of chronic myeloid leukemia marrow

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2404-2410 ◽  
Author(s):  
AG Turhan ◽  
RK Humphries ◽  
CJ Eaves ◽  
MJ Barnett ◽  
GL Phillips ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hematopoietic Cells ◽  
Breakpoint Cluster Region ◽  
Cluster Region ◽  
Differentiated Cells ◽  
The One

Abstract Philadelphia (Ph1) chromosome-positive clonogenic progenitors usually disappear within 4 to 6 weeks in long-term cultures established from the marrow of patients with chronic myeloid leukemia (CML). In contrast, coexisting chromosomally normal hematopoietic cells are relatively well maintained. Thus, even though normal cells are initially undetectable, they may become the predominant population. Recently, we have begun to explore the potential of such cultures as a strategy for preparing CML marrow for autografting, and based on cytogenetic studies of the differential kinetics of Ph1-positive and Ph1-negative clonogenic cells, have chosen a 10-day period in culture to obtain maximal numbers of selectively enriched normal stem cells. Here we present the results of molecular analyses of the cells regenerated in vivo for the initial three CML patients to be treated using this approach by comparison with the differentiated cells generated by continued maintenance of an aliquot of the autograft in vitro (using a slightly modified culture feeding procedure to enhance the production and release of cells into the nonadherent fraction after 4 weeks) for the one patient whose genotype made molecular analysis of clonality status also possible. These analyses showed that cells with a rearranged breakpoint cluster region (BCR) gene were not detectable by Southern blotting in either in vitro or in vivo populations of mature cells that might be assumed to represent the progeny of primitive cells present at the end of the initial 10 days in culture. Production of BCR- negative cells was also shown to be temporally correlated with the appearance of nonclonal hematopoietic cells both in culture and in vivo. These findings provide support for the view that prolonged maintenance of CML marrow cells in long-term culture may allow molecular characterization of both the BCR-genotype and clonality status of cells with in vivo regenerative potential.

α1-Acid glycoprotein expressed in the plasma of chronic myeloid leukemia patients does not mediate significant in vitro resistance to STI571

Blood ◽  
2002 ◽  
Vol 99 (2) ◽  
pp. 713-715 ◽  
Author(s):  
Heather G. Jørgensen ◽  
Moira A. Elliott ◽  
Elaine K. Allan ◽  
Christine E. Carr ◽  
Tessa L. Holyoake ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Plasma Proteins ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Drug Efficacy ◽  
Acid Glycoprotein ◽  
Proliferation In Vitro ◽  
Normal Controls

Abstract Despite the efficacy of STI571 (Glivec, Novartis, Basle, Switzerland) in treating chronic myeloid leukemia (CML), drug resistance has already been noted both in vitro and in vivo. As plasma proteins, including alpha-1-acid glycoprotein (AGP), may reduce drug efficacy through binding, AGP was investigated for its ability to interact with STI571.  At all stages of CML, AGP plasma level was significantly higher than in normal controls (P < .05). The glycoprotein was purified from normal plasma and individual chronic myeloid leukemia (CML) patients' plasma by low-pressure chromatography. The influence of α1-acid glycoprotein (AGP), in the presence of STI571, on the proliferation of Philadelphia chromosome–positive (Ph+) cells was examined. Normal AGP, even at supraphysiological concentrations, did not block the effect of STI571 on K562-cell proliferation in vitro. Moreover, CML-derived AGP failed to block the effect of STI571 on Ph+ cells in vitro. Thus, these in vitro findings suggest that AGP will not abrogate the antileukemic activity of STI571.

Selective elimination of leukemic CD34+ progenitor cells by cytotoxic T lymphocytes specific for WT1

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2198-2203 ◽  
Author(s):  
Liquan Gao ◽  
Ilaria Bellantuono ◽  
Annika Elsässer ◽  
Stephen B. Marley ◽  
Myrtle Y. Gordon ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Chronic Myeloid Leukemia ◽  
T Lymphocytes ◽  
Progenitor Cells ◽  
Cytotoxic T Lymphocytes ◽  
Colony Formation ◽  
Myeloid Leukemia ◽  
Leukemia Cell

Abstract Hematologic malignancies such as acute and chronic myeloid leukemia are characterized by the malignant transformation of immature CD34+ progenitor cells. Transformation is associated with elevated expression of the Wilm's tumor gene encoded transcription factor (WT1). Here we demonstrate that WT1 can serve as a target for cytotoxic T lymphocytes (CTL) with exquisite specificity for leukemic progenitor cells. HLA-A0201– restricted CTL specific for WT1 kill leukemia cell lines and inhibit colony formation by transformed CD34+ progenitor cells isolated from patients with chronic myeloid leukemia (CML), whereas colony formation by normal CD34+ progenitor cells is unaffected. Thus, the tissue-specific transcription factor WT1 is an ideal target for CTL-mediated purging of leukemic progenitor cells in vitro and for antigen-specific therapy of leukemia and other WT1-expressing malignancies in vivo.

scholarly journals Anticancer Activity of Andrographolide Semisynthetic Derivatives

2010 ◽  
Vol 5 (5) ◽  
pp. 1934578X1000500 ◽  
Author(s):  
Vidya Menon ◽  
Sujata Bhat
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Myeloid Leukemia ◽  
Cancer Cell Line ◽  
Maximum Activity ◽  
In Vitro Activity ◽  
Cancer Models ◽  
In Vivo Antitumor Activity

Andrographolide 1, a diterpene lactone of Andrographis paniculata, displays in vitro and in vivo antitumor activity against breast cancer models and mouse myeloid leukemia (M1) cells. In the present study, we report the semi-synthesis of andrographolide derivatives and their in vitro activity against A549 (ATCC) (NSCL cancer) cell line. Amongst the derivatives tested, compounds 3- 5 displayed maximum activity, with IC50 values of 22-31 μg/mL.

Functional Alterations of NKT Cells in Chronic Myeloid Leukemia Patients Can Be Reversed by Imatinib Mesylate In Vitro.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2128-2128
Author(s):  
Alexis Rossignol ◽  
Anne Barra ◽  
Francois Guilhot ◽  
Ali G. Turhan ◽  
Jean-Marc Gombert
Keyword(s):  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Proliferative Response ◽  
Nkt Cells ◽  
Nkt Cell ◽  
Healthy Donors ◽  
Cytogenetic Remission

Abstract Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of the pathognomonic Philadelphia chromosome and the chimeric BCR-ABL oncoprotein with deregulated tyrosine kinase activity. It has been shown previously that T cell immunity contributes to the control of CML, and several arguments suggest an implication of NKT cells in this anti-tumoral immunity. We thus compared frequency, phenotype and functions of blood NKT cells (defined by the CD1d tetramer+ Vα24+ staining) in healthy subjects and patients with CML. Three groups of patients were studied, including Patients in chronic phase (CP) (either at diagnosis or unresponsive to treatment) patients in major/complete cytogenetic remission induced by interferon-alpha (IFN-α) or patients in major/complete cytogenetic remission induced by imatinib mesylate (IM, a specific inhibitor of the BCR-ABL tyrosine kinase). Our results showed that blood NKT cells frequency was not significantly different between healthy donors (n = 17), CP patients (n = 14) and IM-treated patients (n = 16) (0.062 % versus 0.079 % versus 0.041 % respectively). On the other hand, this frequency defined as above was found to be dramatically decreased in patients in complete remission after IFN-α therapy ( 0.01 %, n = 15 patients). We have then analyzed from the phenotypic point of view NKT cells from these three groups. This ex vivo phenotypic study showed that NKT phenotype (expression of CCR7 and CD161) was clearly modified in the IFN-treated group as compared to IM-treated or CP patients and healthy donors, with a clear enrichment in CD161-CCR7+ NKT cells (49% versus 26%, 22% and18% respectively). This CD161-CCR7+ phenotype has been described as the central memory T cell phenotype, with increased lymph-node homing and antigen-presenting cell-stimulating capacities. We have then performed functional studies of NKT cells measuring their proliferative response to α-galactosylceramide (αGC) as a specific triggering antigen. NKT proliferative response to α-GC was abolished in CP patients (2-fold expansion versus 83-fold in healthy donors). This functional impairment was found to be restored in patients treated with IM and in patients treated with IFN-α (106-fold and 20-fold expansion respectively), although this latter group had a strongly depleted NKT compartment. More interestingly, the incubation of CP CML cells in the presence of IM (0.5 and 1 micromolar, n = 5) led to the partial restoration of the NKT cell reactivity to α-GC (29-fold expansion versus α-GC alone). Thus, our results suggest that IFN-α therapy leads to the generation of "central memory-like phenotype" NKT cells, which could play an important role in the long-term remissions observed in these patients. Moreover, our results strongly suggest that IM is able to partially restore the antigenic-response of CML NKT cells in vitro and in vivo, suggesting a role of BCR-ABL in the anergic state of these cells as this was observed at diagnosis. The IM-induced restoration of NKT cell proliferation defect in CP patients suggest that the antileukemic effect of IM could also be partially due to this action in vivo. Cellular mechanisms involved in this phenomenon are currently under study.

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