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1.
Cancers (Basel) ; 16(2)2024 Jan 10.
Article in English | MEDLINE | ID: mdl-38254786

ABSTRACT

We have previously shown that heterotrimeric G-protein subunit alphai2 (Gαi2) is essential for cell migration and invasion in prostate, ovarian and breast cancer cells, and novel small molecule inhibitors targeting Gαi2 block its effects on migratory and invasive behavior. In this study, we have identified potent, metabolically stable, second generation Gαi2 inhibitors which inhibit cell migration in prostate cancer cells. Recent studies have shown that chemotherapy can induce the cancer cells to migrate to distant sites to form metastases. In the present study, we determined the effects of taxanes (docetaxel), anti-androgens (enzalutamide and bicalutamide) and histone deacetylase (HDAC) inhibitors (SAHA and SBI-I-19) on cell migration in prostate cancer cells. All treatments induced cell migration, and simultaneous treatments with new Gαi2 inhibitors blocked their effects on cell migration. We concluded that a combination treatment of Gαi2 inhibitors and chemotherapy could blunt the capability of cancer cells to migrate and form metastases.

2.
Eur J Med Chem ; 252: 115298, 2023 Apr 05.
Article in English | MEDLINE | ID: mdl-36966651

ABSTRACT

Here, we report on the design, synthesis, and biological evaluation of a new theranostic antibody drug conjugate (ADC), Cy5-Ab-SS-SN38, that consists of the HER2-specific antibody trastuzumab (Ab) connected to the near infrared (NIR) pentamethine cyanine dye Cy5 and SN38, which is a bioactive metabolite of the anticancer drug irinotecan. SN38 is bound to an antibody through a glutathione-responsive self-immolative disulfide carbamate linker. For the first time, we explored this linker in ADC and found that it to reduce the drug release rate, which is important for safe drug delivery. The developed ADC exhibited specific accumulation and nanomolar anti-breast cancer activity on HER2-positive (HER2+) cell lines but no effect on HER2-. Animals treated with this ADC exhibited good tolerance. In vivo studies have shown that the ADC had good targeting ability for HER2+ tumors with much higher anticancer potency than trastuzumab itself or a mixture of trastuzumab with SN38. Side-by-side HER2+/HER2-xenograft at the 10 mg/kg dose exhibited specific accumulation and reduction of HER2+ tumor but not accumulation or growth inhibition of HER2-counterpart. The self-immolative disulfide linker implemented in this study was proven to be successful, broadening its utilization with other antibodies for targeted anticancer therapy in general. We believe that the theranostic ADCs comprising the glutathione-responsive self-immolative disulfide carbamate linker are applicable for the treatment and fluorescent monitoring of malignancies and anticancer drug delivery.


Subject(s)
Antineoplastic Agents , Breast Neoplasms , Immunoconjugates , Animals , Humans , Female , Trastuzumab/pharmacology , Trastuzumab/therapeutic use , Precision Medicine , Receptor, ErbB-2/metabolism , Cell Line, Tumor , Xenograft Model Antitumor Assays , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use , Glutathione
3.
Photodiagnosis Photodyn Ther ; 37: 102722, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35032703

ABSTRACT

A facile synthesis, biological evaluation and photodynamic properties of novel activatable anticancer molecular hybrids (chimeras) Ch and I-Ch are described. The chimeras consist of DNA methylating methyl triazene moiety and fluorogenic xanthene-cyanine (XCy) or iodinated xanthene-cyanine (I-XCy) photosensitizer. These two anticancer core structures are bound by means of a self-immolative 4-aminobenzyl alcohol linker. The hydrolytic cleavage of the carbamate protecting group promotes activation of both DNA methylating monomethyl triazene and phototoxic xanthene-cyanine dye providing, in addition, a near-IR emission signal for detection of the drug activation events. Preliminary antiproliferative assay demonstrates that the developed chimeras exhibit higher antitumor activity in the breast cancer cell line upon near-IR light irradiation compared to their structural constituents, xanthene-cyanine photosensitizer and monomethyl triazene substance.


Subject(s)
Photochemotherapy , Photosensitizing Agents , Humans , Cell Line, Tumor , DNA/chemistry , Photochemotherapy/methods , Photosensitizing Agents/pharmacology , Xanthenes/chemistry
4.
Eur J Med Chem ; 225: 113811, 2021 Dec 05.
Article in English | MEDLINE | ID: mdl-34507011

ABSTRACT

A DNA intercalating agent Amonafide interferes with topoisomerase 2 (Topo II) activity and prevents re-ligation of DNA strands, leading to double strand breaks (DSB). If DSB repair fails, cells stop dividing and eventually die. In a search of approaches to enhance anti-cancer activities of Topo II inhibitors, we hypothesized that introduction of additional damage in proximity to the DSB may suppress DNA repair and enhance cancer cell killing. Accordingly, chimeric molecules were created that target a DNA alkylating component to the proximity of Topo II-induced DSBs. These chimeras consist of Amonafide or its 4-amino isomer, and DNA methylating methyl triazene moiety Azene protected with a carbamate group, connected via linker. Treatment of cancer cells with the chimeric molecules leads to significantly higher number of DSBs, which were repaired slower compared to Amonafide or monomethyl triazene-treated cells. On the other hand, methyl triazene linked to non-intercalating Amonafide analogs was ineffective. Together, these data strongly support our hypothesis. In line with increased DSBs, the chimeric molecules exhibited significantly higher antiproliferative activity in cancer cell lines compared to Amonafide or monomethyl triazene constituent Azene. We utilized the fluorescent properties of chimera Amonafidazene to develop ''photo-switchable'' reporting system to monitor the prodrug activation. Using this approach, we found that the chimera accumulated and was activated at the tumor sites specifically and demonstrated significantly stronger tumor suppressing activities compared to Amonafide in a xenograft model. Therefore, targeting alkylating groups to the proximity of DSB sites may become an effective approach towards enhancing anti-cancer activities of inhibitors of topoisomerases.


Subject(s)
Adenine/pharmacology , Antineoplastic Agents/pharmacology , DNA, Neoplasm/drug effects , Organophosphonates/pharmacology , Adenine/chemical synthesis , Adenine/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , DNA Breaks, Double-Stranded/drug effects , DNA Repair , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Male , Methylation , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Organophosphonates/chemical synthesis , Organophosphonates/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured
5.
Chem Biol Drug Des ; 97(2): 237-252, 2021 02.
Article in English | MEDLINE | ID: mdl-32772433

ABSTRACT

The efficient synthesis of molecular hybrids including a DNA-intercalating 9-anilinoacridine (9-AnA) core and a methyl triazene DNA-methylating moiety is described. Nucleophilic aromatic substitution (SN Ar) and electrophilic aromatic substitution (EAS) reactions using readily accessible starting materials provide a quick entry to novel bifunctional anticancer molecules. The chimeras were evaluated for their anticancer activity. Chimera 7b presented the highest antitumor activity at low micromolar IC50 values in antiproliferative assays performed with various cancer cell lines. In comparison, compound 7b outperformed DNA-intercalating drugs like amsacrine and AHMA. Mechanistic studies of chimera 7b suggest a dual mechanism of action: methylation of the DNA-repairing protein MGMT associated with the triazene structural portion and Topo II inhibition by intercalation of the acridine core.


Subject(s)
Amsacrine/analogs & derivatives , Antineoplastic Agents/chemical synthesis , Triazenes/chemistry , Amsacrine/chemistry , Amsacrine/metabolism , Amsacrine/pharmacology , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , DNA/chemistry , DNA/metabolism , DNA Topoisomerases, Type II/chemistry , DNA Topoisomerases, Type II/metabolism , Drug Screening Assays, Antitumor , Humans , Intercalating Agents/chemistry , Intercalating Agents/metabolism , Intercalating Agents/pharmacology , Structure-Activity Relationship , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/metabolism , Triazenes/metabolism , Triazenes/pharmacology
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