Crocin and Flavocoxid Inhibit Tumor Growth, Alter Cytokine Levels of (IL-10/Tnf-α), and Promote Caspase-Induced Apoptosis, and Doxorubicin Efficacy

<i>Background</i>: We assessed the differential sole and Doxorubicin-(Doxo)-combined chemotherapy of the phytomedicines Crocin and Flavocoxid-(flvcox), against the-mouse-Ehrlich-Ascites-Carcinoma-solid-tumor-model-(EAC). We further identified the underlying-molecular mechanisms of actions, interrelations of probed signals, as well as the relative-potency among all used drug modalities. <i>Methods</i>: Functional studies evaluated tumor-burden, animal-survival, serum/tumor redox-status, and levels of key-effectors coherent with tumorigenesis, inflammation, and host-immunity, namely (serum IL-10 and TNF-α) and with tumor-apoptosis (Caspase-3-expression). Furthermore, histopathological examinations were performed to envisage the associated structural changes. <i>Results</i>: EAC-bearing mice had significantly raised serum-TNF-α and tumor lipid-peroxide (MDA) levels, but lower serum IL-10-levels and total serum antioxidant-capacity-(TAC), thereby showing animal-fatalities after-3-weeks. Crocin administration significantly-shrank tumor-mass by (50%), -reduced tumor lipid-peroxide-(MDA) and serum-TNF-α levels; but raised serum-IL-10, TAC and tumor-caspase-3 levels; ultimately augmenting animal survival by (79%). Flvcox had weaker survival-effects (44%) than that of crocin. Correlation studies showed IL-10, contrary to TNF-α to boost animal-survival, and suppress tumor-size. Tumor caspase-3 levels augmented both animal-survival and the TAC-level, while opposed tumor-weight and tumor-MDA levels. Besides, tumor oxidative-stress boosted tumor growth, and reduced caspase-3 levels, thereby worsening animal survival. Histopathology analyses confirmed functional studies. <i>Conclusions</i>: 1)- The study reveals that Doxo confers superior cytotoxicity but inferior cytokine-balance, redox-status and animal-rescuing profiles; 2)- Crocin and Flvcox elicit prominent sole- and combined-cytotoxicity, and animal-rescuing potentials, by restoring the disrupted-balance of the cytokines (IL-10/TNF-α), optimizing serum/tumor redox-potentials and accelerating tumor-cell apoptosis; 3)- Cross-talk was evidently documented among (key-cytokines), (tumor-burden), (redox-status), and (tumor-apoptosis), in a manner that dictates the efficacy of sole (or) mutual-therapy, and their influence on animal-survival in response to cancer.