Current Cancer Drug Targets - Volume 23, Issue 4, 2023

The previous year's worldview for cancer treatment has advanced from general to more precise therapeutic approaches. Chemotherapies were first distinguished as the most reliable and brief therapy with promising outcomes in cancer patients. However, patients could also suffer from severe toxicities resulting from chemotherapeutic drug usage. An improved comprehension of cancer pathogenesis has led to new treatment choices, including tumor-targeted therapy and immunotherapy. Subsequently, cancer immunotherapy and targeted therapy give more hope to patients since their combination has tremendous therapeutic efficacy. The immune system responses are also initiated and modulated by targeted therapies and cytotoxic agents, which create the principal basis that when targeted therapies are combined with immunotherapy, the clinical outcomes are of excellent efficacy, as presented in this review. This review focuses on how immunotherapy and targeted therapy are applicable in cancer management and treatment. Also, it depicts promising therapeutic results with more extensive immunotherapy applications with targeted therapy. Further elaborate that immune system responses are also initiated and modulated by targeted therapies and cytotoxic agents, which create the principal basis that this combination therapy with immunotherapy can be of great outcome clinically.

Aim: Abnormal glycosylation often occurs in tumor cells. T-synthase (core 1 beta 1,3- galactosyltransferase, C1GALT1, or T-synthase) is a key enzyme involved in O-glycosylation. Although T-synthase is known to be important in human tumors, the effects of T-synthase and T-antigen on human tumor responses remain poorly defined. Methods: In this study, a T-synthase-specific short hairpin RNA (shRNA) or T-synthase-specific eukaryotic expression vector(pcDNA3.1(+)) was transfected into murine Osteosarcoma LM8 cells to assess the effects of T-synthase on T cells and cytokines. Results: The up-regulation of T-synthase promoted the proliferation of osteosarcoma cells in vitro, but it promoted the proliferation of tumor initially up to 2-3 weeks but showed significant growth inhibitory effect after 3 weeks post-implantation in vivo. Osteosarcoma cells with high T-synthase expression in vitro promoted the proliferation and inhibited the apoptosis of CD8⁺ T cells. Further, T-synthase upregulation promoted CD8⁺ T-cell proliferation and the increased production of CD4⁺ T cell-derived IFN-γ cytokines to induce the increased tumor lethality of CTLs. Conclusion: Our data suggest that high T-synthase expression inhibits tumor growth by improving the body's anti-tumor immunity. Therefore, using this characteristic to prepare tumor cell vaccines with high immunogenicity provides a new idea for clinical immunotherapy of osteosarcoma.

Aims: Development of anticancer agents targeting tubulin protein. Background: Tubulin protein is being explored as an important target for anticancer drug development. Ligands binding to the colchicine binding site of the tubulin protein act as tubulin polymerization inhibitors and arrest the cell cycle in the G2/M phase. Objective: Synthesis and screening of benzotriazole-substituted 2-phenyl quinazolines as potential anticancer agents. Methods: A series of benzotriazole-substituted quinazoline derivatives have been synthesized and evaluated against human MCF-7 (breast), HeLa (cervical) and HT-29 (colon) cancer cell lines using standard MTT assays. Results: ARV-2 with IC50 values of 3.16 μM, 5.31 μM, 10.6 μM against MCF-7, HELA and HT29 cell lines, respectively displayed the most potent antiproliferative activities in the series while all the compounds were found non-toxic against HEK293 (normal cells). In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, ARV-2 and ARV-3 were found to induce mitochondria-mediated apoptosis. Conclusion: The benzotriazole-substituted 2-phenyl quinazolines have the potential to be developed as potent anticancer agents.

Background: Novel therapeutic strategies are urgently required to improve clinical outcomes of gastric cancer (GC). KIF15 cooperates with KIF11 to promote bipolar spindle assembly and formation, which is essential for proper sister chromatid segregation. Therefore, we speculated that the combined inhibition of KIF11 and KIF15 might be an effective strategy for GC treatment. Hence, to test this hypothesis, we aimed to evaluate the combined therapeutic effect of KIF15 inhibitor KIF15- IN-1 and KIF11 inhibitor ispinesib in GC. Methods: We validated the expression of KIF11 and KIF15 in GC tissues using immunohistochemistry and immunoblotting. Next, we determined the effects of KIF11 or KIF15 knockout on the proliferation of GC cell lines. Finally, we investigated the combined effects of the KIF11 and KIF15 inhibitors both in vitro and in vivo. Results: KIF11 and KIF15 were overexpressed in GC tissues than in the adjacent normal tissues. Knockout of either KIF11 or KIF15 inhibited the proliferative and clonogenic abilities of GC cells. We found that the KIF15 knockout significantly increased ispinesib sensitivity in GC cells, while its overexpression showed the opposite effect. Further, using KIF15-IN-1 and ispinesib together had a synergistic effect on the antitumor proliferation of GC both in vitro and in vivo. Conclusion: This study shows that the combination therapy of inhibiting KIF11 and KIF15 might be an effective therapeutic strategy against gastric cancer.

Background: Malignant tumors continue to remain a main global public health issue. In the past 40 years, due to strides made in multi-disciplinary comprehensive treatment schemes for patients suffering from malignant tumors, especially chemotherapy schemes, the survival rate has been greatly improved in such patients. This group can be expected to maintain their fertility or have restored endocrine function following successful malignant tumor treatment. Therefore, focusing on the ovarian damage caused by chemotherapy in women of childbearing age is vital in order to protect their fertility and improve their quality of life. Objective: This study attempted to evaluate whether VX-765 possesses an ovarian protective effect in ovarian injury induced by chemotherapy in the mice model. Methods: Female C57BL/6J mice were administered with VX-765 gavage once a day for 21 consecutive days. Use of cyclophosphamide (Cy) began one week after the last gavage administration of VX- 765. Detailed classification of follicles at various levels was then quantified in each group. Immunohistochemistry and Western blot analysis were then used in order to analyze the expression of key proteins (FOXO3a, mTOR, RPS6 and AKT) as well as their phosphorylation of the PI3K / PTEN / AKT pathways in the ovary. The concentrations of AMH were measured by ELISA. Results: The follicles at all levels of Cy treated mice were less than those of the normal group (P < 0.05). Meanwhile, mice treated with VX-765 prior to receiving Cy treatment had more primordial follicles (PMF) than mice treated with Cy alone (P < 0.05). In early growing follicles (EGF) and antral follicles (AF), no difference was observed among the experimental groups (P > 0.05), however, they were lower than those in the normal group (P < 0.05). In mice treated with continuous Cy, the total follicle number (TF) of mice combined with VX-765 (C-Cy-Vx765) was higher than that of mice without VX-765, and the TF of the two groups was lower than that of the normal group (P < 0.05). The value of PMF/TF in C-Cy-Vx765 group was significantly higher than that in the other three groups, while that of EGF/TF was significantly lower (P < 0.05). Immunohistochemical results showed that the phosphorylated forms of the main proteins of the PI3K / PTEN / AKT pathway were found to be more positive in Cy treated mice. The Western blot analysis showed that when Cy and VX-765 were cotreated, the increased levels of these phosphorylated proteins decreased compared with those treated with Cy alone. The AMH level of infancy Cy and VX-765 co-treated mice was higher than that of infancy normal mice (P < 0.05). After the mice grew to sexual maturity, the AMH level of Cy and VX- 765 co-treated mice was still higher than that of Cy treated mice (P < 0.05), and there was no significant difference with normal mice (P > 0.05). Conclusion: VX-765 can maintain the level of AMH and inhibit the recruitment of PMF, thus protecting mice from Cy induced gonadotropic toxicity. Accordingly, VX-765 may play a protective role in mice with ovarian injury caused by chemotherapy.

Background: Our research aimed to clarify the role of genetic polymorphisms in GST (T1 and M1) in the development of Ph-ve CML. Materials and Methods: We report on a case-control study with 126 participants, divided into 26 patients with Ph-ve CML (57.7% male, 42.3% female) and 100 healthy volunteers (51% male, 49% female) with no medical history of cancer as a control population. All Ph-ve CML patients were diagnosed according to standard hematologic and cytogenetic criteria based on CBC, confirmed by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) to determine the presence or absence of the BCRABL gene, followed by bone marrow (BM) examination. Results: Of the 26 studied cases, 50% had the GSTT1 null genotype against 21% of the control group, a statistically significant difference (CI= 1.519 - 9.317; p-value= 0.004). The GSTM1 null genotype was detected in 23.1% of cases and 35% of controls, a difference not statistically significant (OR= 0.557; CI= 0.205-1.515; p-value= 0.252). The distribution of GSTT1 and GSTM1 polymorphisms was also examined according to gender, age and ethnic grouping; these findings revealed no statistically significant differences. Conclusion: Our study reveals a strong correlation between GSTT1 polymorphism and Ph-ve CML, whereas the data for GSTM1 polymorphisms indicates no role in the initial development of the disease. More studies are required to further clarify these and other genes' roles in disease development.

Background: At present, the treatment of hepatocellular carcinoma (HCC) is disturbed by the treatment failure and recurrence caused by the residual liver cancer stem cells (CSCs). Therefore, drugs targeting HCC CSCs should be able to effectively eliminate HCC and prevent its recurrence. In this study, we demonstrated the effect of Polyphyllin VII (PP7) on HCC CSCs and explored their potential mechanism. Methods: HepG2 and Huh7 cells were used to analyze the antitumor activity of PP7 by quantifying cell growth and metastasis as well as to study the effect on stemness. Results: Our results demonstrated that PP7 promoted apoptosis and significantly inhibited proliferation and migration of both HepG2 and Huh7 cells. PP7 also inhibited tumor spheroid formation and induced significant changes in the expression of stemness markers (CD133 and OCT-4). These effects of PP7 were mediated by STAT3 signaling. Conclusion: PP7 can effectively suppress tumor initiation, growth, and metastasis and inhibit stemness through regulation of STAT3 signaling pathway in liver cancer cells. Our data would add more evidence to further clarify the therapeutic effect of PP7 against HCC.