As a platinum-containing anticancer drug, cisplatin is the keystone for treating many malignancies. Nephrotoxicity is the main dose-limiting toxicity, and several hydration therapies and supplementary strategies are utilized to reduce cisplatin-induced kidney damage, so the discovery and development of effective and safe antitumor drugs are still on the path of human health. Herein, a new four-coordinated Pt complex [Pt(TSC)Cl] using N(4)-phenyl-2-formylpyridine thiosemicarbazone (HTSC) was synthesized and characterized by single-crystal X-ray diffraction, 1HNMR, FT-IR, LC/MS and CHN elemental analysis. The Pt(TSC)Cl complex revealed antiproliferative activity against A549, MCF-7 and Caco-2 cell lines with a low micromolar IC50 (200–1.75 µM). Specifically, the Pt(TSC)Cl complex displayed more selectivity in Caco-2 cells (IC50 = 2.3 µM) than cisplatin (IC50 = 107 µM) after 48 h of treatment. Moreover, compared with cisplatin, a known nephrotoxic drug, the Pt(TSC)Cl complex exhibited lower nephrotoxicity against Hek293 normal cells. We also found that the Pt(TSC)Cl complex can effectively prevent cancer cell propagation in sub-G1 and S phases and induce apoptosis (more than 90%). Real time PCR and western analysis demonstrated that the expression pattern of apoptotic genes and proteins is according to the intrinsic apoptosis pathway through the Bax/Bcl-2-Casp9-Casp3/Casp7 axis. Collectively, our findings indicated that the Pt(TSC)Cl complex triggers apoptosis in Caco-2 cell lines, while low nephrotoxicity was shown and may be considered a useful anticancer drug candidate for colorectal cancers for further optimization and growth.
Immunotherapy is considered a promising approach for cancer treatment. An important strategy for cancer immunotherapy is the use of cancer vaccines, which have been widely used for cancer treatment. Despite the great potential of cancer vaccines for cancer treatment, their therapeutic effects in clinical settings have been limited. The main reason behind the lack of significant therapeutic outcomes for cancer vaccines is believed to be the immunosuppressive tumor microenvironment (TME). The TME counteracts the therapeutic effects of immunotherapy and provides a favorable environment for tumor growth and progression. Therefore, overcoming the immunosuppressive TME can potentially augment the therapeutic effects of cancer immunotherapy in general and therapeutic cancer vaccines in particular. Among the strategies developed for overcoming immunosuppression in TME, the use of toll-like receptor (TLR) agonists has been suggested as a promising approach to reverse immunosuppression. In this paper, we will review the application of the four most widely studied TLR agonists including agonists of TLR3, 4, 7, and 9 in cancer immunotherapy.
Recently, combination therapies have become a promising option with hopeful therapeutic outcomes due to their strong antitumor effects. Among them, despite the great success of cancer chemoimmunotherapy, it has not been able to improve the outcome of patients. Immunosuppressive tumor microenvironment (TME) has been recognized as the main barrier to immunotherapy. So, it has been assumed that targeting HIF-1α as a reshaping of TME combined with chemoimmunotherapy can capably enhance the antitumor response of therapy. Herein, we have studied the therapeutic effects of HIF-1α inhibition combined with chemoimmunotherapy. We established CT26 mouse models to assess the synergistic effect of genetic silencing of HIF-1α combined with oxaliplatin (OXA) and imiquimod (IMQ) on tumor growth and TME. We showed that in comparison with dual combination therapy, mice treated with triple combination therapy exhibited a significant delay in tumor growth, which was correlated with high levels of cellular immune-related cytokines. Besides, mice without HIF-1α siRNA treatment exhibited high tumor growth and high levels of immunosuppressive factors, indicating an immunosuppressive phenotype. Briefly, we found that HIF-1α inhibition could synergize with OXA and IMQ to inhibit tumor growth in vivo. Our data suggest that targeting HIF-1α represents a promising strategy to enhance the antitumor response of chemoimmunotherapy.
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