Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer

Hermanowicz, Justyna Magdalena; Szymanowska, Anna; Sieklucka, Beata; Czarnomysy, Robert; Pawlak, Krystyna; Bielawska, Anna; Bielawski, Krzysztof; Kałafut, Joanna; Przybyszewska, Alicja; Surażyński, Arkadiusz; Rivero-Müller, Adolfo; Pawlak, Dariusz

doi:10.1080/14756366.2021.1879803

Cited by 22 publications

(38 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genetic similarities with humans lead to zebrafish often being used as a strong and cost-effective animal model for cancer research and the discovery of cancer drugs. The small size, transparency of zebrafish embryos, easy manipulation, short testing period, and small amount of tested drugs are undoubtedly important aspects giving zebrafish an advantage over the mouse/rat model of cancer [ 36 ]. An antiproliferative test showed that PtMet2–PAMAM possessed the most biological activity, which was much higher than that of PtMet2.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanism of Anticancer Action of Novel Imidazole Platinum(II) Complex Conjugated with G2 PAMAM-OH Dendrimer in Breast Cancer Cells

Czarnomysy

Muszyńska

Rok

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Transition metal coordination compounds play an important role in the treatment of neoplastic diseases. However, due to their low selectivity and bioavailability, as well as the frequently occurring phenomenon of drug resistance, new chemical compounds that could overcome these phenomena are still being sought. The solution seems to be the synthesis of new metal complexes conjugated with drug carriers, e.g., dendrimers. Numerous literature data have shown that dendrimers improve the bioavailability of the obtained metal complexes, solving the problem of their poor solubility and stability in an aqueous environment and also breaking down inborn and acquired drug resistance. Therefore, the aim of this study was to synthesize a novel imidazole platinum(II) complex conjugated with and without the second-generation PAMAM dendrimer (PtMet2–PAMAM and PtMet2, respectively) and to evaluate its antitumor activity. Cell viability studies indicated that PtMet2–PAMAM exhibited higher cytotoxic activity than PtMet2 in MCF-7 and MDA-MB-231 breast cancer cells at relatively low concentrations. Moreover, our results indicated that PtMet2–PAMAM exerted antiproliferative effects in a zebrafish embryo model. Treatment with PtMet2–PAMAM substantially increased apoptosis in a dose-dependent manner via caspase-9 (intrinsic pathway) and caspase-8 (extrinsic pathway) activation along with pro-apoptotic protein expression modulation. Additionally, we showed that apoptosis can be induced by activating POX, which induces ROS production. Furthermore, our results also clearly showed that the tested compounds trigger autophagy through p38 pathway activation and increase Beclin-1, LC3, AMPK, and mTOR inhibition. The high pro-apoptotic activity and the ability to activate autophagy by the imidazole platinum(II) complex conjugated with a dendrimer may be due to its demonstrated ability to reverse multidrug resistance (MDR) and thereby increase cellular accumulation in breast cancer cells.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Zebrafish embryos were obtained from mating adults, maintained, and raised as described previously [ 36 ]. Zygote period cleaving eggs were transferred to six-well plastic cell culture plates filled with embryo medium E3.…”

Section: Methodsmentioning

confidence: 99%

Mechanism of Anticancer Action of Novel Imidazole Platinum(II) Complex Conjugated with G2 PAMAM-OH Dendrimer in Breast Cancer Cells

Czarnomysy

Muszyńska

Rok

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…The starting material for the preparation of the new tricyclic sulfonamide MM131 was the corresponding chlorosulfone derivative 1 (Scheme 1) which was obtained by multistage synthesis according to the procedures described in the literature [25][26][27][28][29][30][31]. Thus, obtained compound 1 was mixed with the (R)-enantiomer of 2-amino-propan-1-ol in anhydrous acetonitrile at room temperature.…”

Section: Chemistrymentioning

confidence: 99%

The Anticancer Action of a Novel 1,2,4-Triazine Sulfonamide Derivative in Colon Cancer Cells

et al. 2021

Self Cite

View full text Add to dashboard Cite

Cancer therapy is one of the most important challenges of modern medical and chemical sciences. Among the many methods of combating cancer, chemotherapy plays a special role. Imperfect modern chemotherapy justifies continuing the search for new, more effective, and safe drugs. Sulfonamides are the classic group of chemotherapeutic drugs with a broad spectrum of pharmacological activity. Recent literature reports show that sulfonamide derivatives have anti-tumor activity in vitro and in vivo. The aim of the study was to synthesize a novel 1,2,4-triazine sulfonamide derivative and check its anticancer potential in DLD-1 and HT-29 colon cancer cells. The biological studies included MTT assay, DNA biosynthesis, cell cycle analysis, Annexin V binding assay, ethidium bromide/acridine orange staining, and caspase-8, -9, and -3/7 activity. The concentrations of important molecules (sICAM-1, mTOR, Beclin-1, cathepsin B) involved in the pathogenesis and poor prognosis of colorectal cancer were also evaluated by ELISA. We demonstrated that the novel compound was able to induce apoptosis through intrinsic and extrinsic pathways and was capable of decreasing sICAM-1, mTOR, cathepsin B concentrations, whereas increased Beclin-1 concentration was detected in both colon cancer cell lines. The novel compound represents promising multi-targeted potential in colorectal cancer, but further in vivo examinations are needed to confirm the claim.

show abstract

“…When the tumors reached a diameter of about 5 mm, that is, according to the literature the size suitable to conduct further phases of research, the intraperitoneal administration of MM-129 (2.5 mg/kg), 5-FU (50 mg/kg), or their combination was started [28]. The dose was chosen based on our preliminary study, in which we assessed the anticancer activity of MM-129 [9,29]. The control group was administered with MM-129 solvent (10% DMSO/PBS).…”

Section: Establishment Of Xenograftmentioning

confidence: 99%

“…Our previous in vitro observations have clearly shown that MM-129 is more effective than the hitherto used preparations, including the reference drug 5-fluorouracil. It statistically significantly reduces cell viability and inhibits DNA biosynthesis of DLD-1 and HT-29 colorectal cancer cell [9]. The phosphoinositide-3-kinase (PI3K)/AKT/mTOR pathway plays a key role in the regulation of processes related to cell growth, metabolism, survival, and proliferation.…”

Section: Introductionmentioning

confidence: 99%

MM-129 as a Novel Inhibitor Targeting PI3K/AKT/mTOR and PD-L1 in Colorectal Cancer

Hermanowicz

Pawlak

Sieklucka

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

Background and aims: The purpose of the present study was to examine the pharmacodynamics features of MM-129 (1,2,4-triazine derivative) as a novel promising drug candidate against colon cancer. Methods: MM-129 was assessed for antitumor activity through an in vivo study on Cby.Cg-Foxn1nu/cmdb mice. The mechanistic studies investigated cellular affinity of a new 1,2,4-triazine derivative by measuring levels of intracellular/extracellular signal molecules participating in tumorigenesis. Results: The results revealed that MM-129 significantly reduced tumor growth in mice challenged with DLD-1 and HT-29 cells. It exerted the ability to inhibit intracellular molecules promoting tumorigenesis and inducing cell cycle arrest, like Akt, mTOR, and CDK2. Simultaneously, it was able to downregulate PD-L1 expression, which involves immunological self-tolerance. Combined administration of MM-129 and 5-fluorouracil (5-FU) additionally amplified these effects, which were manifest as an increase population of cells in the G0/G1 phase. Conclusions: A novel 1,2,4-triazine derivative with a dual mechanism of antitumor activity—MM-129, may act as a chemosensitizer, overcoming chemoresistance against 5-FU, the first-line agent in the chemotherapy of colon cancer.

show abstract

Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer

Cited by 22 publications

References 48 publications

Mechanism of Anticancer Action of Novel Imidazole Platinum(II) Complex Conjugated with G2 PAMAM-OH Dendrimer in Breast Cancer Cells

Mechanism of Anticancer Action of Novel Imidazole Platinum(II) Complex Conjugated with G2 PAMAM-OH Dendrimer in Breast Cancer Cells

The Anticancer Action of a Novel 1,2,4-Triazine Sulfonamide Derivative in Colon Cancer Cells

MM-129 as a Novel Inhibitor Targeting PI3K/AKT/mTOR and PD-L1 in Colorectal Cancer

Contact Info

Product

Resources

About