Targeting the key players of phenotypic plasticity in cancer cells by phytochemicals.

Plasticity of phenotypic traits refers to an organism's ability to change in response to environmental stimuli. As a result, the response may alter an organism's physiological state, morphology, behavior, and phenotype. Phenotypic plasticity in cancer cells describes the considerable ability of cancer cells to transform phenotypes through non-genetic molecular signaling activities that promote therapy evasion and tumor metastasis via amplifying cancer heterogeneity. As a result of metastable phenotypic state transitions, cancer cells can tolerate chemotherapy or develop transient adaptive resistance. Therefore, new findings have paved the road in identifying factors and agents that inhibit or suppress phenotypic plasticity. It has also investigated novel multitargeted agents that may promise new effective strategies in cancer treatment. Despite the efficiency of conventional chemotherapeutic agents, drug toxicity, development of resistance, and high-cost limit their use in cancer therapy. Recent research has shown that small molecules derived from natural sources are capable of suppressing cancer by focusing on the plasticity of phenotypic responses. This systematic, comprehensive, and critical review analyzes the current state of knowledge regarding the ability of phytocompounds to target phenotypic plasticity at both preclinical and clinical levels. Current challenges/pitfalls, limitations, and future perspectives are also discussed.