tumor resistance

Troglitazone (Romglizone) is a PPARγ agonist with anti-inflammatory and anti-tumor activity.

Milataxel is an orally bioavailable taxane with potential antineoplastic activity. Upon oral administration, milataxel and its major active metabolite M-10 bind to and stabilize tubulin, resulting in the inhibition of microtubule depolymerization and cell division, cell cycle arrest in the G2 M phase, and the inhibition of tumor cell proliferation. Unlike other taxane compounds, milataxel appears to be a poor substrate for the multidrug resistance (MDR) membrane-associated P-glycoprotein (P-gp) efflux pump and may be useful for treating multidrug-resistant tumors. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).This compound is unstable in powder form and other related salt forms are recommended.

1. Linalool (Linalol), a natural compound of the essential oils, has been shown to have antinociceptive, antimicrobial, and anti-inflammatory properties. 2. Linalool was protected against LPS/GalN-induced liver injury through induction of antioxidant defense via Nrf2 activating and reduction inflammatory response via NF-κB inhibition. 3. Linalool biosynthesis and accumulation might be involved in plant defense against bacterial and fungal pathogens and be associated with field resistance to citrus canker. 4. Linalool significantly increased the expression of antioxidant enzymes regulated by Nrf-2 and diminished lung tissue levels of several pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) and interleukin (IL)-6.

1. Sinapine, an alkaloid from seeds of the cruciferous species, can be used as an effective natural compound for chemo-resistance. 2. Sinapine has antioxidant and radio-protective activities.

Uvarigrin induces tumor multidrug resistance cell apoptosis and triggers Caspase-9 activation. Uvarigrin is isolated from the roots of Uvaria calamistrata.

Tetrahydrouridine (NSC-112907; THU) is a multidrug resistance modulator. It can be used in cancer treatment to make tumor cells more sensitive to radiation therapy. THU is a competitive cytidine deaminase(CDA) inhibitor that inhibits deamination in the catabolism of cytotoxic deoxycytidine analogs such as ara-C and Gemcitabine.

LX1, an anti-prostate cancer compound, specifically targets the androgen receptor (AR), AR variants, and the steroidogenic enzyme AKR1C3. It inhibits AKR1C3's enzymatic function, decreases the conversion of androstenedione to testosterone, and reduces the expression of both AR and AR-V7, subsequently downregulating their target genes. Additionally, LX1 is effective in overcoming tumor cell resistance to Enzalutamide, and when combined with Enzalutamide, it further suppresses tumor growth.

MC3629, an inhibitor of the histone methyltransferase (EZH2), exhibits antitumor activity. This compound effectively inhibits the proliferation and self-renewal of SHH MB cancer cells while inducing cell apoptosis (apoptosis). MC3629 is also useful in research on tumor aggressiveness and resistance.

Nic-15 (compound 4n) serves as an anti-constrictive agent targeting the low vascular characteristics of pancreatic tumors. These characteristics enable cancer cells to adapt to the nutrient-deficient tumor microenvironment and develop resistance to treatment. Nic-15 modulates the PI3K Akt mTOR pathway and alleviates ER stress induced by Gemcitabine. It significantly inhibits migration and colony formation in MIA PaCa-2 and PANC-1 pancreatic cancer cells. When used in combination with Gemcitabine, Nic-15 effectively addresses resistance issues in pancreatic tumors. In xenograft models in vivo, Nic-15 notably enhances the efficacy of Gemcitabine.

JND4135, a type II TRK inhibitor, exhibits IC50 values targeting TRKA, TRKB, and TRKC at 2.79, 3.19, and 3.01 nM, respectively. It can overcome resistance due to TRKxDFG and other mutations in the BaF3 stable model, inhibiting the phosphorylation of TRKs WT, xDFG mutations, and their downstream signaling molecules. Additionally, JND4135 induces G0 G1 phase arrest and cell apoptosis (apoptosis) in BaF3–CD74-TRKA-G667C cells. This compound also demonstrates antitumor activity in a BaF3-CD74-TRKA-G667C mouse xenograft model by suppressing tumor growth.

AR antagonist 9 is an orally active, selective androgen receptor (AR) antagonist that inhibits cancer by disrupting the formation of AR ligand-binding domain dimers, showing potential in overcoming drug resistance in prostate cancer (PCa). Its antagonistic activity against AR has an IC50 of 0.051 μM, comparable to Enzalutamide (IC50= 0.060 μM). This compound demonstrates superior inhibitory effects on ARF876L T877A and ARW741C mutants compared to Enzalutamide. Additionally, AR antagonist 9 possesses favorable pharmacokinetic properties, with an oral bioavailability (F) of 66.24% in rats, and significantly inhibits tumor growth in LNCaP xenograft mouse models upon oral administration. AR antagonist 9 holds promise for research in overcoming PCa resistance.

Tesmilifene hydrochloride is an antihistamine and chemosensitizer. It targets cytochrome P450 and exerts a hormone-like effect on DNA synthesis in MCF-7 cells, while also promoting tumor growth in mouse rat models. Tesmilifene hydrochloride is capable of overcoming multidrug resistance.

AB8939 is a potent small-molecule inhibitor of microtubule tubulin polymerization, exhibiting antitumor activity (with tumor cell proliferation inhibition IC50≤10 nM). It effectively circumvents resistance mechanisms mediated by P-glycoprotein and myeloperoxidase. AB8939 can induce G2 M phase cell cycle arrest and apoptosis.

NF-κB-IN-19 (Compound 8) is an NF-κB inhibitor. It effectively induces DNA damage in tumor cells through the NF-κB signaling pathway and promotes the production of reactive oxygen species (ROS), as well as induces autophagy and apoptosis. Additionally, NF-κB-IN-19 inhibits levels of VEGF and HIF-1α, exerting antiproliferative effects in tumor cells through the PI3K AKT and STAT-3 pathways. It is also effective in overcoming cisplatin resistance and exhibits antitumor activity.

Lysosomal P-gp targeted agent 1 (Compound 14) is an antitumor drug that targets lysosomal P-glycoprotein (Pgp). It is selectively transported to lysosomes via overexpressed Pgp, releasing nitric oxide that generates reactive oxygen species (ROS), causing lysosomal membrane permeabilization (LMP) and inducing apoptosis. This compound can overcome resistance mediated by P-glycoprotein, leading to cell cycle arrest while maintaining relatively low toxicity to normal cells. It exhibits antitumor activity by significantly inhibiting tumor growth.

Antitumor agent-200 (Compound 2g) is a microtubule synthesis inhibitor that binds to the colchicine site on tubulin, causing G2/M cell cycle arrest and inducing reactive oxygen species (ROS) production. It demonstrates significant inhibitory activity against P-glycoprotein (P-gp) overexpressing cell lines MCF7/ADR and KBV200, with resistance indices (DRI) of 0.83 and 0.58, respectively. In an MCF-7 xenograft model, Antitumor agent-200 (at 25 mg/kg, administered intraperitoneally) achieves a 57.2% tumor growth inhibition rate. This compound is applicable for research in the field of cancer therapy.

2-Guanidinobenzimidazole (2GBI) is a selective agonist of NLRP3, with a KD value of 1.29 μM for His-GFP-NLRP3. It directly binds to the LRR domain of NLRP3, facilitating the assembly and activation of the inflammasome. Additionally, 2-Guanidinobenzimidazole enhances antitumor immunity, inhibits tumor growth, and overcomes resistance to immune checkpoint blockade (ICB).

P-gp inhibitor 28 (Compound 4h) is an inhibitor of P-glycoprotein (P-gp) that can suppress cancer cell proliferation, with an IC50 value ranging from 15.88 to 21.96 μM in MCF-7/ADR cells. This compound enhances the accumulation of Rho123 in MCF-7/ADR cells and is applicable for research in cancer treatment and overcoming tumor multidrug resistance.

GPV0057 (Compound 5d) is a potent and selective inhibitor of P-glycoprotein (P-gp). It also acts as a selective activator of the potassium channel Kir2.1. By competitively binding at the substrate binding site of P-gp, GPV0057 inhibits ATP-dependent drug efflux, thereby reversing multidrug resistance in tumor cells. Additionally, it stabilizes the open state of Kir2.1, enhancing potassium ion influx. GPV0057 has potential applications in the study of tumors with high P-gp expression and Kir2.1-related diseases, such as heart failure and Andersen-Tawil syndrome.

P-gp modulator-7 (Compound 9e) is an inhibitor of P-glycoprotein (P-gp). It uniquely occupies the channel entrance of P-gp in a T-shaped conformation, blocking the peristaltic extrusion mechanism of transmembrane domains TM12 and TM9. This action inhibits P-gp from pumping drugs out of cells and reverses multidrug resistance (MDR) in tumor cells. P-gp modulator-7 shows promise for cancer research.

DC_AC50 is a dual inhibitor of Atox1 and CCS (copper chaperones), aimed at reducing or preventing acquired chemotherapy resistance by inhibiting intracellular copper chaperones. It binds to Atox1 and CCS, thereby reducing cancer cell proliferation and tumor growth.

Bimiralisib (PI3K-IN-2) is an orally bioavailable pan inhibitor of PI3K and inhibitor of the mTOR, with potential antineoplastic activity. PI3K-IN-2 inhibits the PI3K kinase isoforms alpha, beta, gamma and delta and, to a lesser extent, mTOR kinase, which may result in tumor cell apoptosis and growth inhibition in cells overexpressing PI3K mTOR. Activation of the PI3K mTOR pathway promotes cell growth, survival, and resistance to both chemotherapy and radiotherapy.

(20S)-Protopanaxadiol (20-Epiprotopanaxadiol) (20-Epiprotopanaxadiol), an apoptosis inducer, is an aglycon metabolic derivative of the protopanaxadiol-type ginseng saponin.

Iproplatin is a synthetic second-generation platinum-containing compound related to cisplatin. Iproplatin binds to and forms DNA crosslinks and platinum-DNA adducts, resulting in DNA replication failure and cell death. Although less prone to glutathione i