Exploring the Potential of Metallodrugs as Chemotherapeutics for Triple Negative Breast Cancer

Abstract

This review focuses on studies of coordination and organometallic compounds as potential chemotherapeutics against triple negative breast cancer (TNBC) which has one of the poorest prognoses and worst survival rates from all breast cancer types. At present, chemotherapy is still the standard of care for TNBC since only one type of targeted therapy has been recently developed. References for metal-based compounds studied in TNBC cell lines will be listed, and those of metal-specific reviews, but a detailed overview will also be provided on compounds studied in vivo (mostly in mice models) and those compounds for which some preliminary mechanistic data was obtained (in TNBC cell lines and tumors) and/or for which bioactive ligands have been used. The main goal of this review is to highlight the most promising metal-based compounds with potential as chemotherapeutic agents in TNBC.

Keywords: inorganic chemistry; mechanisms; medicinal chemistry; metallodrugs; triple negative breast cancer (TNBC).

Figure 1.

Proposed anticancer mechanism of action for compound 13 (DNP). Reproduced with permission from Ref. [40]. Copyright 2020, Wiley-VCH.

Figure 2.

Antitumor activity in vivo on MDA-MB-231 xenografts of gold(III)-dithiocarbamato peptidomimetics. Female nude mice bearing MDA-MB-231 tumors were treated with either vehicle (control) or the compounds 26a (AuD6) and 26b (AuD8) at 1 mg kg⁻¹ d⁻¹. A, Inhibition of xenograft growth by both complexes. Tumor volumes were measured every other day using a caliper. Points represent the mean ± SD (bars) of seven mice per group. The insert depicts representative tumors from each treatment group; * = p<0.05. B, if only the most responsive mice are considered, the xenograft growth inhibition is greater. The insert shows average weights of mice over time; ** = p<0.01. C, Immunohistochemical p27 and TUNEL staining of tumor samples indicates proteasome inhibition and apoptosis as a result of both compounds. Stronger p27 staining is observed following 26b (AuD8) treatment, and more TUNEL positive cells are observed following 26a (AuD6) treatment. Brown colored cells are considered positive. Reproduced with permission from Ref. [73]. Copyright 2014, PLOS journals.

Figure 3.

A) % of reduction of tumor burden in a cohort of 12 female NOD.CB17-Prkdc scid/J mice inoculated subcutaneously with 5×10⁶ MDA-MB-231 cells. The treatment started when tumors were palpable (5–6 mm diameter). 6 mice were treated with compound 43 (Ru-IM) (pink bars), 6 were treated with the vehicle 100 μl Normal Saline (0.9% NaCl) (black bars). 43 was administered in the amount of 5 mg/kg/every other day. B) Compound 43 (Ru-IM) ruthenium content in tissues at the end of efficacy study. Data represents mean ± SD. N = 3; * indicates P < 0.05. Reproduced with permission from Ref. [119]. Copyright 2014, ACS journals.

Figure 4.

Schematic of the metal-based compounds explored in TNBC mice models and their major mode of actions. Compounds are indicated by the metal contained and by the number provided to these compounds through the text.

Scheme 1.

A) Platinum (II) compounds used in TNBC clinical trials (cisplatin, oxaliplatin, carboplatin, and lobaplatin)^8,17–22 or, B) in selected preclinical studies (1–5).^[–31]

Scheme 2.

Selected platinum (IV) compounds used in preclinical TNBC studies.^[–40]

Scheme 3.

A palladium (II) used in the clinic for prostate cancer (TOOKAD®) and some selected palladium (II) compounds that have undergone preclinical TNBC studies.^[–53]

Scheme 4.

Auranofin, a gold(I) compound currently being studied in clinical trials for non-small cell lung and ovarian cancer,^[54] and some selected gold, silver and copper compounds that have undergone preclinical TNBC studies.^[–74]

Scheme 5.

Three ruthenium (III derivatives) that underwent clinical trials for colorectal cancer (NAMI-A, KP1019/KP1339), a Ru(II)-based photosensitizer (TLD-1433) with FDA fast track designation in phase II clinical trials for treating non-muscle invasive bladder cancer, and some selected osmium (II) and ruthenium (II) coordination compounds that have undergone preclinical TNBC studies.^{[, –98]}

Scheme 6.

Ruthenium (II) coordination compounds containing biologically active ligands that have undergone preclinical TNBC studies.^{[99, 103, 110, 111, 113]}

Scheme 7.

Ruthenium (II) organometallic that have undergone preclinical TNBC studies.^{[, –128]}

Scheme 8.

Ruthenium (III), Ru(III)/Ru(II) mixed valence, Fe(II) and Fe(III) compounds that have undergone preclinical TNBC studies.^{[–, –155, 157]}

Scheme 9.

Miscellaneous metal-based compounds that have undergone preclinical studies in TNBC cells.^{[165, 167, 170, 171, 174]}