Ascorbate has dose-dependent inverse effects on cancer cells growth and expression of matrixmetalloproteinases (MMP) and transforming growth factor-beta (TGF-beta), which regulate extracellular matrix (ECM) remodeling. We examined melanoma cell viability and ECM remodeling mechanisms of ascorbate and its modulation by an extract from Polypodium leucotomos (PL) (a fern) via the regulation of apoptosis, heat-shock proteins (HSPs), MMP-1 or tissue inhibitors of matrix metalloproteinase-1 (TIMP-1) that inhibits MMP-1. The dose-dependent regulation of cell viability/proliferation by ascorbate was associated with inverse regulation of apoptosis and stimulation of HSPs at growth-inhibitory concentrations. PL antagonized the stimulation of MMP-1, TGF-beta and HSPs by a growth-inhibitory ascorbate dose and stimulated the expression of TIMP-1, while maintaining growth inhibition. We infer that a combination of ascorbate with PL is beneficial to cancer management via the simultaneous inhibition of cell growth and expression of MMP-1, TGF-beta and HSPs, and furthermore, the stimulation of TIMP-1.