The role of minimal residual disease and serum free light chain ratio in the management of multiple myeloma.

Multiple myeloma (MM) denotes a cancerous growth characterized by abnormal proliferation of plasma cells. Growing evidence suggests that the complexity in addressing MM lies in the presence of minimal residual disease (MRD) within the body. MRD assessment is becoming increasingly important for risk assessment in patients with MM. Similarly, the levels of serum free protein light chain and their ratio play a crucial role in assessing the disease burden and changes in MM. In this paper, we review and explore the utilization of MRD and serum free light chain ratio in the treatment of MM, delving into their respective characteristics, advantages, disadvantages, and their interrelation.

Development of a series of flurbiprofen and zaltoprofen platinum(IV) complexes with anti-metastasis competence targeting COX-2, PD-L1 and DNA.

To develop new anti-metastasis chemotherapeutic drugs, a series of flurbiprofen (FLP) and zaltoprofen (ZTP) platinum(IV) complexes targeting COX-2, PD-L1 and DNA was prepared and investigated. Complex 2 with dual FLP ligands displays promising antitumor activities in vitro and exhibits much potential in overcoming drug resistance. More importantly, the antitumor evaluation in vivo demonstrates that complex 2 possesses promising inhibition of cancer growth and metastasis simultaneously. Further investigation of the mechanism revealed the multi-specific antitumor function of complex 2. It exerts remarkable DNA damage after reduction to platinum(II) complex, and up-regulates the expression of p53 and γ-H2AX. Then, complex 2 promotes mitochondria-mediated apoptosis effectively by activating the Bcl-2/Bax/caspase3 pathway. Furthermore, inflammation in tumor tissues is restrained by the suppression of enzymes COX-2, MMP-9, NLRP3 and caspase1, which would favor the inhibition of tumor metastasis. Moreover, compound 2 boosts T-cell immunity by restraining PD-L1 expression, and further improving the density of CD3+ and CD8+ T cells in tumor tissues.

Ketoprofen and Loxoprofen Platinum(IV) Complexes Displaying Antimetastatic Activities by Inducing DNA Damage, Inflammation Suppression, and Enhanced Immune Response.

Metastasis is a major contributor of death in cancer patients, and there is an urgent need for effective treatments of metastatic malignancies. Herein, ketoprofen (KP) and loxoprofen (LP) platinum(IV) complexes with antiproliferative and antimetastatic properties were designed and prepared by integrating chemotherapy and immunotherapy targeting cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), and programmed death ligand 1 (PD-L1), besides DNA. A mono-KP platinum(IV) complex with a cisplatin core is screened out as a candidate possessing potent anti-proliferative and anti-metastasis activities both in vitro and in vivo. It induces serious DNA damage and further leads to high expression of γ-H2AX and p53. Moreover, it promotes apoptosis of tumor cells through mitochondrial apoptotic pathway Bcl-2/Bax/caspase3. Then, COX-2, MMP-9, NLRP3, and caspase1 as pivotal enzymes igniting inflammation and metastasis are obviously inhibited. Notably, it significantly improves immune response through restraining the expression of PD-L1 to increase CD3+ and CD8+ T infiltrating cells in tumor tissues.

Albumin-encapsulated Nanoparticles of Naproxen Platinum(IV) Complexes with Inflammation Inhibitory Competence Displaying Effective Antitumor Activities in vitro and in vivo.

BACKGROUND: Platinum(IV) complexes with inflammation inhibitory properties are much favored in improving antitumor activities. Nanodrug-delivery system as a preferable measure for antitumor therapy are widely explored in platinum(IV) drug delivery. PURPOSE: The aim for this study was to develop novel bovine serum albumin (BSA) nanoparticles (NPs) based on naproxen platinum(IV) complexes to display a synergistic antitumor mechanism targeting cyclooxygenase-2 (COX-2), metalloproteinase-9 (MMP-9) and inducible nitric oxide synthase (iNOS). METHODS: Herein, we reported the preparation of two BSA NPs of naproxen platinum(IV) complexes, and their antitumor activities were investigated in vitro and in vivo. RESULTS: Both NPs possessed relatively uniform size and good stability for 30 days in aqueous solution. They exhibited prominent antitumor activities in vitro, and showed great potential in reversing drug resistance. Furthermore, these two NPs played superior tumor growth suppression in vivo in contrast to the free compounds, which were comparable to that of cisplatin and oxaliplatin, but induced lower toxic influences than platinum(II) drugs especially to spleen and liver. Moreover, the naproxen platinum(IV) NPs could decrease tumor inflammation targeting COX-2, MMP-9 and iNOs, and decreasing NO production, which would be in favor of enhancing the antitumor competence, and reducing toxicity. CONCLUSION: Taken together, BSA NPs of naproxen platinum(IV) complexes demonstrated a powerful antitumor efficacy in vitro and in vivo. The platinum(IV) NPs with inflammation inhibitory competence targeting multiple enzymes reported in this work afford a new strategy for the development of antitumor therapy to overcome drawbacks of clinical platinum(II) drugs.

Design, synthesis and biological evaluation of dihydro-2-quinolone platinum(iv) hybrids as antitumor agents displaying mitochondria injury and DNA damage mechanism.

The design of novel platinum(iv) complexes with mitochondria injury competence, besides the DNA damage mechanism, is a promising way to develop new platinum drugs. Herein, dihydro-2-quinolone (DHQLO) as a mitocan was incorporated into the platinum(iv) system for the first time to prepare a new series of DHQLO platinum(iv) compounds. Complex 1b could effectively inhibit the proliferation of tumor cells in vitro and in vivo. It accumulated at higher levels in both whole cells and DNA, and easily underwent intercellular reduction to release platinum(ii) and DHQLO moieties. The released platinum(ii) complex caused serious DNA damage by covalent conjunction with the DNA duplex, and remarkably increased the expression of the γ-H2AX protein. Moreover, 1b also caused serious mitochondria injury to induce mitochondrial membrane depolarization and increase ROS generation. Such actions upon DNA and mitochondria activate the p53 apoptotic pathway synergetically in tumor cells by upregulating the protein p53 and apoptotic proteins caspase9 and caspase3, which efficiently promoted the apoptotic death of tumor cells. Compound 1b with such synergic mechanism exhibited great potential in reversing cisplatin resistance and improving antitumor efficacies.

Naproxen platinum(iv) hybrids inhibiting cycloxygenases and matrix metalloproteinases and causing DNA damage: synthesis and biological evaluation as antitumor agents in vitro and in vivo.

Cycloxygenases (COXs) and matrix metalloproteinases (MMPs) in the tumor microenvironment (TME) are tightly related to the progression of cancers. Here, naproxen as a potent inhibitor of both COX and MMP was combined with platinum(iv) to construct hybrids as antitumor agents. Compound 2 with comparable or even superior activities to that of cisplatin, oxaliplatin, and carboplatin, great potential for reversing drug resistance, and superior tumor targeting properties was screened out as a lead compound. Moreover, compound 2 possessed potent tumor growth inhibition capability in vivo, which was comparable to that of oxaliplatin, and displayed rather lower side effects than the platinum(ii) reference drugs. The naproxen platinum(iv) complex could easily undergo reduction and liberate the platinum(ii) complex and naproxen as well as exert a multifunctional antitumor mechanism: (i) the liberated platinum(ii) fragment would cause serious DNA injury; (ii) naproxen would inhibit COX-2 and decrease tumor-associated inflammation; and (iii) the naproxen platinum(iv) complex exhibited remarkable MMP-9 inhibition in tumor tissues. These antitumor functions can help reduce the growth and metastasis of malignancy.