Natural products play a critical role in the discovery and development of numerous drugs for the treatment of various types of cancer. These phytochemicals have demonstrated anti-carcinogenic properties by interfering with the initiation, development, and progression of cancer through altering various mechanisms such as cellular proliferation, differentiation, apoptosis, angiogenesis, and metastasis. Treating multifactorial diseases, such as cancer with agents targeting a single target, might lead to limited success and, in many cases, unsatisfactory outcomes. Various epidemiological studies have shown that the steady consumption of fruits and vegetables is intensely associated with a reduced risk of cancer. Since ancient period, plants, herbs, and other natural products have been used as healing agents. Likewise, most of the medicinal ingredients accessible today are originated from the natural resources. Regardless of achievements, developing bioactive compounds and drugs from natural products has remained challenging, in part because of the problem associated with large-scale sequestration and mechanistic understanding. With significant progress in the landscape of cancer therapy and the rising use of cutting-edge technologies, we may have come to a crossroads to review approaches to identify the potential natural products and investigate their therapeutic efficacy. In the present review, we summarize the recent developments in natural products-based cancer research and its application in generating novel systemic strategies with a focus on underlying molecular mechanisms in solid cancer.

Prostate cancer (PCa) remains a critical global health challenge, with high mortality rates and significant heterogeneity, particularly in advanced stages. While early-stage PCa is often manageable with conventional treatments, metastatic PCa is notoriously resistant, highlighting an urgent need for precise biomarkers and innovative therapeutic strategies. This review focuses on the dualistic roles of sirtuins, a family of NAD+-dependent histone deacetylases, dissecting their unique contributions to tumor suppression or progression in PCa depending on the cellular context. It reveals their multifaceted impact on hallmark cancer processes, including sustaining proliferative signaling, evading growth suppressors, activating invasion and metastasis, resisting cell death, inducing angiogenesis, and enabling replicative immortality. SIRT1, for example, fosters chemoresistance and castration-resistant prostate cancer through metabolic reprogramming, immune modulation, androgen receptor signaling, and enhanced DNA repair. SIRT3 and SIRT4 suppress oncogenic pathways by regulating cancer metabolism, while SIRT2 and SIRT6 influence tumor aggressiveness and androgen receptor sensitivity, with SIRT6 promoting metastatic potential. Notably, SIRT5 oscillates between oncogenic and tumor-suppressive roles by regulating key metabolic enzymes; whereas, SIRT7 drives PCa proliferation and metabolic stress adaptation through its chromatin and nucleolar regulatory functions. Furthermore, we provide a comprehensive summary of the roles of individual sirtuins, highlighting their potential as biomarkers in PCa and exploring their therapeutic implications. By examining each of these specific mechanisms through which sirtuins impact PCa, this review underscores the potential of sirtuin modulation to address gaps in managing advanced PCa. Understanding sirtuins’ regulatory effects could redefine therapeutic approaches, promoting precision strategies that enhance treatment efficacy and improve outcomes for patients with aggressive disease.

Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by rapid progression, pronounced chemoresistance, and a complex network of genetic and epigenetic dysregulation. Within this challenging context, sirtuins, NAD⁺-dependent deacetylases, have emerged as pivotal modulators of key cellular processes that drive pancreatic cancer progression. Each sirtuin contributes uniquely to PDAC pathogenesis. SIRT1 influences apoptosis and chemoresistance through hypoxia, enhancing glycolytic metabolism and HIF-1α signaling, which sustain tumor survival against drugs like gemcitabine. SIRT2, conversely, disrupts cancer cell proliferation by inhibiting eIF5A, while SIRT3 exerts tumor-suppressive effects by regulating mitochondrial ROS and glycolysis. SIRT4 inhibits aerobic glycolysis, and its therapeutic upregulation has shown promise in curbing PDAC progression. Furthermore, SIRT5 modulates glutamine and glutathione metabolism, offering an avenue to disrupt PDAC’s metabolic dependencies. SIRT6 and SIRT7, through their roles in angiogenesis, EMT, and metastasis, represent additional targets, with modulators of SIRT6, such as JYQ-42, showing potential to reduce tumor invasiveness. This review aims to provide a comprehensive exploration of the emerging roles of sirtuins, a family of NAD⁺-dependent enzymes, as critical regulators within the oncogenic landscape of pancreatic cancer. This review meticulously explores the nuanced involvement of sirtuins in pancreatic cancer, elucidating their contributions to tumorigenesis and suppression through mechanisms such as metabolic reprogramming, the maintenance of genomic integrity and epigenetic modulation. Furthermore, it emphasizes the urgent need for the development of targeted therapeutic interventions aimed at precisely modulating sirtuin activity, thereby enhancing therapeutic efficacy and optimizing patient outcomes in the context of pancreatic malignancies.

Cervical cancer tumors with undetectable HPV (HPV^U) have been underappreciated in clinical decision making. In this study, two independent CC datasets were used to characterize the largest cohort of HPV^U tumors to date (HPV^U = 35, HPV⁺ = 430). Genomic and transcriptome tumor profiles and patient survival outcomes were compared between HPV⁺ and HPV^U tumors. In vitro analyses were done to determine efficacy of the selective CDK4/6 inhibitor palbociclib on HPV^U cancer cell lines. Patients with HPV^U CC tumors had worse progression-free and overall survival outcomes compared to HPV⁺ patients. TP53, ARID1A, PTEN, ARID5B, CTNNB1, CTCF, and CCND1 were identified as significantly mutated genes (SMGs) enriched in HPV^U tumors, with converging functional roles in cell cycle progression. In vitro HPV^U, but not HPV⁺, cancer cell lines with wild type RB1 were sensitive to palbociclib monotherapy. These results indicate that HPV^U status can be translated into the clinic as a predictive biomarker of poor patient response to standard of care treatments. We suggest primary cervix tumors be routinely tested for HPV prior to treatment to identify patients who will benefit from more aggressive precision-driven therapy. Our results identify palbociclib as a lead candidate as an alternative treatment strategy for HPV^U CC patients.

Persistent HPV infection is causative for the majority of cervical cancer cases; however, current guidelines do not require HPV testing for newly diagnosed cervical cancer. Using an institutional cohort of 88 patients with cervical cancer treated uniformly with standard-of-care chemoradiation treatment (CRT) with prospectively collected clinical outcome data, we observed that patients with cervical tumors containing HPV genotypes other than HPV 16 have worse survival outcomes after CRT compared with patients with HPV 16 ⁺ tumors, consistent with previously published studies. Using RNA sequencing analysis, we quantified viral transcription efficiency and found higher levels of E6 and the alternative transcript E6*I in cervical tumors with HPV genotypes other than HPV 16. These findings were validated using whole transcriptome data from The Cancer Genome Atlas ( n = 304). For the first time to our knowledge, transcript expression level of HPV E6*I was identified as a predictive biomarker of CRT outcome in our complete institutional data set ( n = 88) and within the HPV 16 ⁺ subset ( n = 36). In vitro characterization of HPV E6*I and E6 overexpression revealed that both induce CRT resistance through distinct mechanisms dependent upon p53–p21. Our findings suggest that high expression of E6*I and E6 may represent novel biomarkers of CRT efficacy, and these patients may benefit from alternative treatment strategies.