The Rosellinia sanctae-cruciana extract was subjected to detailed liquid chromatography tandem mass spectrometry studies. A total of 38 peaks were annotated to m/z 508.26, m/z 510.28, m/z 524.26, m/z 526.28, m/z 540.26, m/z 542.27, and m/z 584.28 [M + H]⁺. The accurate mass, mutually supported UV/vis spectra, and database search identified these compounds as cytochalasins. Systematic dereplication helped identify a peak at m/z 540.26 [M + H]⁺ as the new compound. Further, the identified compound was purified by high-performance liquid chromatography and characterized by 2D NMR to be 19,20-epoxycytochalasin N1, a new optical isomer of 19,20-epoxycytochalasin-N. It exhibited substantial cytotoxicity with IC₅₀ values ranging from 1.34 to 19.02 μM. This study shows a fast approach for dereplicating and identifying novel cytochalasin metabolites in crude extracts.

β-Boswellic acid (β-BA), a potent NF-kB signaling pathway inhibitor, has shown synergistic anti-cancerous activity (NCT03149081, NCT00243022 and NCT02977936) in various clinical trials as complementary therapies. The study has been conducted to investigate the effect and efficacy of 2-pyridin-4-yl methylene β-boswellic acid (PMBA) and 5-Flourouracil (5-FU) in combination therapy for the treatment of KRAS mutant colon cancer. Analysis of isobologram showed synergistic combination index (CI > 1) of PMBA and 5-FU against the HCT-116^G13D and SW-620^G12V cell lines. The growth-inhibiting PMBA also caused apoptosis mediating effects with dose-dependent increase in caspase-3 activity, while inhibiting the formation of colonies in combination with 5-FU. As evident, PMBA affected colorectal 3D CSC properties including the ability to self-renew along with the expression of multi-drug resistance genes, viz., ABCB1, ABCC1 and ALDH1A1, ALDH1A2, ALDH1A3, ALDH3A1, and CSC markers like CD44, CD166, EPCAM, OCT-4, SOX-2, and NANOG compared with those in 2D model explaining the expression pattern of oncogenic KRAS^{G13D, G12V} mutation. When examined for plasma level of PMBA (20 mg) and PMBA+5-FU (20 + 40 mg), a time-dependent increase in the level of the drug (5-FU) was detected, indicating its absorption and bioavailability with excellent half-life of the PMBA for both routes of administration (IV and Oral), thereby indicating a new adjuvant therapy for KRAS mutant colon cancer.

Seven cytochalasins, 19,20-epoxycytochalasin N, cytochalasin P1, deacetyl 19,20-epoxycytochalasin C, 19,20-epoxycytochalasin D, 19,20-epoxycytochalasin C, cytochalasin D, and cytochalasin C, were isolated from a fungal (Rosellinia sanctae-cruciana) crude extract. A cytotoxicity assay (sulforhodamine B) was performed on a series of cancer cell lines: HT-29, A-549, PC-3, HCT-116, SW-620, and MCF-7. Simultaneously, the liquid chromatography–mass spectrometry (LC–MS)/MS profile of 19,20-epoxycytochalasin C-treated cell lines revealed that 19,20-epoxycytochalasin C (m/z 524.25) oxidized to a metabolite of m/z 522.25 Da (−2 Da (−2H) from 19,20-epoxycytochalasin C). Further chemical oxidation of 19,20-epoxycytochalasin C using the Dess–Martin reagent produced an identical metabolite. It has been noticed that the parent molecule (19,20-epoxycytochalasin C) showed an IC₅₀ of 650 nM (on HT-29), whereas for the oxidized metabolite (m/z 522.24) of 19,20-epoxycytochalasin C, the IC₅₀ was >10 μM. It is clear that the parent molecule had 16 times higher cytotoxic potential as compared to the oxidized metabolite. The spectroscopic investigation indicated that the oxidation of the hydroxyl (−OH) group occurred at the C7 position in 19,20-epoxycyctochalsin C and led to the inactivation of 19,20-epoxycytochalasin C. Further, cell cycle analysis and histopathological evidence support the findings, and CDK2 could be a possible target of 19,20-epoxycyctochalasin C.

Cancer is a chaos of uncontrolled cell proliferation that has consistently invented new circuitry programs to operate inside the cell machinery. Globally, cancer statistics account for 65% of mortality worldwide, mainly due to the adoption of lifestyle behaviours. In 2020, FDA approved 40 new drugs, out of which 16 (40%) were approved as cancer drugs. Overall, the risk of dying from cancer decreased, but further reductions in cancer death rates can be accelerated by applying existing cancer control knowledge across all the population segments, emphasising those in the lowest socio-economic and other disadvantaged population. Various therapeutic regimes, including low-molecular-weight inhibitors, targeting oncogenic signaling pathways are under development. However, the pitfall of targeted therapies is the quick emergence of acquired drug resistance encumbered with toxic side effects. Several FDA acclaimed therapeutic legacies or biosimilars earmarked signaling pathways of rare diseases (cystic fibrosis, erythropoietic protoporphyria, neuromyelitis optica spectrum disorder, tenosynovial giant cell tumor, sickle cell disease, systemic sclerosis-associated interstitial lung disease, muscular dystrophy), neurological and psychiatric disorders, infectious diseases, heart, lung, circulatory, endocrine diseases, autoimmune conditions, cancers and blood disorders. When cancer progresses, these signals develop specific characteristics that can be targeted for anti-cancer therapy. The designer inhibitors have emerged as novel pharmaceutical interventions that aim to block the pathways in an effort to reverse the abnormal phenotype of the cancer cells. Numerous cell-signaling channels have evolved and invigorated to make off three-dimensional feedback networks. The magnitude of accessible information by pathways occupies curated information as a consortium. To fully appreciate the pivotal roles that signaling cascades play in tumor development, it is necessary to understand the involved signaling cascades in the interaction between cancer cells. The prime endeavour is to canonically curate all signaling pathways involving cell cycle, EGFR, MAPK, GPCR, PI3K/ AKT/mTOR, immune checkpoints, nuclear receptors, janus kinase, transcription activators etc., involving the manipulation of genetic and nuclear receptors. Here, we will summarize the vast amount of information describing the signals that mediate crosstalk between cancer cells and the targets related to this crosstalk.

This manuscript reports a chemical investigation involving reverse-phase semipreparative HPLC-based isolation, followed by mass spectrometric and NMR-based characterization of three endophytic fungi recovered from Albizia lebbeck (L.) Benth. The study yielded two compounds (1-2) from ALE-75 (Sacharicola bicolor), three (3-5) from ALE-85 (Aspergillus pseudoglaucus), and one (6) from ALE-121 (Aspergillus eurotium). The extract from Aspergillus pseudoglaucus exhibited antioxidant potential (IC50 = 11.92 µg/mL in DPPH assay) and moderate cytotoxicity against lung (A549, IC50 = 35 µg/ml), colon (HCT-116, IC50 value of 45.4 µg/ml), and breast (T47D, IC50 value of 2.8 µg/ml) cancer cells, with growth inhibition of 89%, 77%, and 74% at 100 µg/ml. ALE-121 extract showed strong cytotoxicity against lung (A549, IC50 = 11.2 µg/ml), colon (HCT-116, IC50 = 12.5 µg/ml) and breast (T47D, IC50 = 15 µg/ml) cancer cells, with inhibition rates of 85%, 84%, and 75% at 100 µg/ml. Compound 6 (Austrocortinin) showed strong cytotoxicity against these cancer lines, with inhibition rates of 89%, 87%, and 67% at 10 µg/ml. Compound 1 was initially identified through the fermentation process of the endophytic fungus Coriolopsis sp. J5, which was isolated from the mangrove Ceriops tagal and compound 2 in Penicillium chrysogenum LF066 from the marine sponge Tethya aurantium. Compounds 3-5, originally found in Chaetomium globosum and Aspergillus flavus, whereas Compound 6 was initially discovered in the Australian Cortinarius toadstool. Although these compounds have been identified previously, this is the first instance of their reporting in the aforementioned endophytic fungi isolated from Albizia lebbeck.